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Dave, Sandeep S.

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1999

M.D. — Northwestern University

Medical Resident, Medicine

Northwestern University

Fellow in Hematology-Oncology, Medicine

National Institutes of Health

News:

Grants:

Viral Oncology Training Grant

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1980
End Date
June 30, 2024

Duke CTSA (KL2)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Duke CTSA (TL1)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Postdoctoral Training in Genomic Medicine Research

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
June 14, 2017
End Date
May 31, 2022

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

Genetic and genomic signatures of long-term radiation exposure in non-human primates

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
Wake Forest University School of Medicine
Role
Principal Investigator
Start Date
September 30, 2015
End Date
September 29, 2020

Understanding the Context-Dependent Roles of Mutations in Lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 18, 2009
End Date
August 31, 2020

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2020

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Defining the Functional Role of Mutations in Diffuse Large B cell Lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2020

Administrative Supplements for P30 CCSG

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Project Leader
Start Date
January 01, 2015
End Date
December 31, 2019

AZD9668 and Neutrophil Elastase Inhibition to Prevent Graft-versus-Host Disease

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 09, 2018
End Date
November 30, 2019

Phase 1 Trial of Panobinostat + Ruxolitnib for Relapsed/Refactory Diffused Large B Cell Lymphoma (DLBCL)

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Mentor
Start Date
March 01, 2016
End Date
August 31, 2019

Viral Oncology Training Grant

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1980
End Date
June 30, 2019

Genomic Predictors of Response in Mantle Cell Lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
March 01, 2018
End Date
February 28, 2019

The Tumor Suppressive Role of ID3 in Burkitt Lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
March 01, 2018
End Date
February 28, 2019

Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 15, 2016
End Date
August 31, 2018

Dissecting the role of injury is sarcoma formation

Administered By
Pediatrics, Hematology-Oncology
Role
Collaborator
Start Date
July 01, 2015
End Date
August 31, 2017

Dissecting the role of injury is sarcoma formation

Administered By
Pediatrics, Hematology-Oncology
Role
Collaborator
Start Date
July 01, 2015
End Date
August 31, 2017

HARDAC+:Reproducible HPC for next-generation genomics

Administered By
Duke Center for Genomic and Computational Biology
Role
Major User
Start Date
April 15, 2016
End Date
April 14, 2017

The genetics of hepatosplenic T cell lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2017

Genetic determinants of progression in chronic lymphocytic leukemia

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
November 01, 2012
End Date
October 31, 2016

Novel combinations to overcome resistance to histone deacetylase inhibitors in lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2016

Predicting Treatment Futility in Refractory Diffuse Large B cell Lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2015

Clinico-Genomic Assessment of Performance Status in Elderly AML Patients

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 01, 2012
End Date
August 31, 2015

Exome-wide screening for common mutations in lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 10, 2011
End Date
May 31, 2013
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Publications:

TET2 Deficiency Sets the Stage for B-cell Lymphoma.

TET2 is a well-established tumor suppressor in the context of myeloid malignancies, but its role in lymphoma development has been less clear. In this issue of Cancer Discovery, Dominguez and colleagues report that TET2 function is critical for germinal center exit and plasma cell differentiation, and its deficiency can lead to B-cell lymphoma phenotypes.See related article by Dominguez et al., p. 1632.

Authors
Shingleton, JR; Dave, SS
MLA Citation
Shingleton, Jennifer R., and Sandeep S. Dave. “TET2 Deficiency Sets the Stage for B-cell Lymphoma..” Cancer Discov, vol. 8, no. 12, Dec. 2018, pp. 1515–17. Pubmed, doi:10.1158/2159-8290.CD-18-1143.
PMID
30510015
Source
pubmed
Published In
Cancer Discov
Volume
8
Issue
12
Publish Date
2018
Start Page
1515
End Page
1517
DOI
10.1158/2159-8290.CD-18-1143

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma.

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. Our understanding of PEL is poor and therefore treatment strategies are lacking. To address this need, we conducted genome-wide CRISPR/Cas9 knockout screens in eight PEL cell lines. Integration with data from unrelated cancers identifies 210 genes as PEL-specific oncogenic dependencies. Genetic requirements of PEL cell lines are largely independent of Epstein-Barr virus co-infection. Genes of the NF-κB pathway are individually non-essential. Instead, we demonstrate requirements for IRF4 and MDM2. PEL cell lines depend on cellular cyclin D2 and c-FLIP despite expression of viral homologs. Moreover, PEL cell lines are addicted to high levels of MCL1 expression, which are also evident in PEL tumors. Strong dependencies on cyclin D2 and MCL1 render PEL cell lines highly sensitive to palbociclib and S63845. In summary, this work comprehensively identifies genetic dependencies in PEL cell lines and identifies novel strategies for therapeutic intervention.

Authors
Manzano, M; Patil, A; Waldrop, A; Dave, SS; Behdad, A; Gottwein, E
MLA Citation
Manzano, Mark, et al. “Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma..” Nat Commun, vol. 9, no. 1, Aug. 2018. Pubmed, doi:10.1038/s41467-018-05506-9.
PMID
30111820
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
3263
DOI
10.1038/s41467-018-05506-9

Genetic convergence of rare lymphomas.

PURPOSE OF REVIEW: We review the genetic foundations of different rare lymphomas to examine their shared origins. These data indicate the potential application of genomics to improve the diagnosis and treatment of these rare diseases. RECENT FINDINGS: Next generation sequencing technologies have provided an important window into the genetic underpinnings of lymphomas. A growing body of evidence indicates that although some genetic alterations are specific to certain diseases, others are shared across different lymphomas. Many such genetic events have already demonstrated clinical utility, such as BRAF V600E that confers sensitivity to vemurafenib in patients with hairy cell leukemia. SUMMARY: The rareness of many lymphoma subtypes makes the conduct of clinical trials and recruitment of significant numbers of patients impractical. However, a knowledge of the shared genetic origins of these rare lymphomas has the potential to inform 'basket' clinical trials in which multiple lymphoma subtypes are included. These trials would include patients based on the presence of alterations in targetable driver genes. Such approaches would be greatly strengthened by a systematic assessment of significant patient numbers from each subtype using next generation sequencing.

Authors
Shingleton, JR; Dave, SS
MLA Citation
Shingleton, Jennifer R., and Sandeep S. Dave. “Genetic convergence of rare lymphomas..” Curr Opin Hematol, vol. 25, no. 4, July 2018, pp. 307–14. Pubmed, doi:10.1097/MOH.0000000000000435.
PMID
29702524
Source
pubmed
Published In
Curr Opin Hematol
Volume
25
Issue
4
Publish Date
2018
Start Page
307
End Page
314
DOI
10.1097/MOH.0000000000000435

Plasmodium parasite exploits host aquaporin-3 during liver stage malaria infection.

Within the liver a single Plasmodium parasite transforms into thousands of blood-infective forms to cause malaria. Here, we use RNA-sequencing to identify host genes that are upregulated upon Plasmodium berghei infection of hepatocytes with the hypothesis that host pathways are hijacked to benefit parasite development. We found that expression of aquaporin-3 (AQP3), a water and glycerol channel, is significantly induced in Plasmodium-infected hepatocytes compared to uninfected cells. This aquaglyceroporin localizes to the parasitophorous vacuole membrane, the compartmental interface between the host and pathogen, with a temporal pattern that correlates with the parasite's expansion in the liver. Depletion or elimination of host AQP3 expression significantly reduces P. berghei parasite burden during the liver stage and chemical disruption by a known AQP3 inhibitor, auphen, reduces P. falciparum asexual blood stage and P. berghei liver stage parasite load. Further use of this inhibitor as a chemical probe suggests that AQP3-mediated nutrient transport is an important function for parasite development. This study reveals a previously unknown potential route for host-dependent nutrient acquisition by Plasmodium which was discovered by mapping the transcriptional changes that occur in hepatocytes throughout P. berghei infection. The dataset reported may be leveraged to identify additional host factors that are essential for Plasmodium liver stage infection and highlights Plasmodium's dependence on host factors within hepatocytes.

Authors
Posfai, D; Sylvester, K; Reddy, A; Ganley, JG; Wirth, J; Cullen, QE; Dave, T; Kato, N; Dave, SS; Derbyshire, ER
MLA Citation
Posfai, Dora, et al. “Plasmodium parasite exploits host aquaporin-3 during liver stage malaria infection..” Plos Pathog, vol. 14, no. 5, May 2018. Pubmed, doi:10.1371/journal.ppat.1007057.
Website
https://hdl.handle.net/10161/16762
PMID
29775485
Source
pubmed
Published In
Plos Pathog
Volume
14
Issue
5
Publish Date
2018
Start Page
e1007057
DOI
10.1371/journal.ppat.1007057

Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection.

A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αβ T cells and suppress the expansion of innate-like αβ T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional αβ T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional αβ T cells.

Authors
Roy, S; Moore, AJ; Love, C; Reddy, A; Rajagopalan, D; Dave, SS; Li, L; Murre, C; Zhuang, Y
MLA Citation
Roy, Sumedha, et al. “Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection..” Front Immunol, vol. 9, 2018. Pubmed, doi:10.3389/fimmu.2018.00042.
PMID
29416542
Source
pubmed
Published In
Frontiers in Immunology
Volume
9
Publish Date
2018
Start Page
42
DOI
10.3389/fimmu.2018.00042

Epstein-Barr Virus Induces Adhesion Receptor CD226 (DNAM-1) Expression during Primary B-Cell Transformation into Lymphoblastoid Cell Lines.

Epstein-Barr virus (EBV), an oncogenic herpesvirus, infects and transforms primary B cells into immortal lymphoblastoid cell lines (LCLs), providing a model for EBV-mediated tumorigenesis. EBV transformation stimulates robust homotypic aggregation, indicating that EBV induces molecules that mediate cell-cell adhesion. We report that EBV potently induced expression of the adhesion molecule CD226, which is not normally expressed on B cells. We found that early after infection of primary B cells, EBV promoted an increase in CD226 mRNA and protein expression. CD226 levels increased further from early proliferating EBV-positive B cells to LCLs. We found that CD226 expression on B cells was independent of B-cell activation as CpG DNA failed to induce CD226 to the extent of EBV infection. CD226 expression was high in EBV-infected B cells expressing the latency III growth program, but low in EBV-negative and EBV latency I-infected B-lymphoma cell lines. We validated this correlation by demonstrating that the latency III characteristic EBV NF-κB activator, latent membrane protein 1 (LMP1), was sufficient for CD226 upregulation and that CD226 was more highly expressed in lymphomas with increased NF-κB activity. Finally, we found that CD226 was not important for LCL steady-state growth, survival in response to apoptotic stress, homotypic aggregation, or adhesion to activated endothelial cells. These findings collectively suggest that EBV induces expression of a cell adhesion molecule on primary B cells that may play a role in the tumor microenvironment of EBV-associated B-cell malignancies or facilitate adhesion in the establishment of latency in vivo. IMPORTANCE Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency is modeled in the laboratory by infecting B cells from the blood of normal human donors in vitro. In this model, we identified a protein called CD226 that is induced by EBV but is not normally expressed on B cells. Rather, it is known to play a role in aggregation and survival signaling of non-B cells in the immune system. Cultures of EBV-infected cells adhere to one another in "clumps," and while the proteins that are responsible for this cellular aggregation are not fully understood, we hypothesized that this form of cellular aggregation may provide a survival advantage. In this article, we characterize the mechanism by which EBV induces this protein and its expression on lymphoma tissue and cell lines and characterize EBV-infected cell lines in which CD226 has been knocked out.

Authors
Grossman, L; Chang, C; Dai, J; Nikitin, PA; Jima, DD; Dave, SS; Luftig, MA
MLA Citation
Grossman, Lisa, et al. “Epstein-Barr Virus Induces Adhesion Receptor CD226 (DNAM-1) Expression during Primary B-Cell Transformation into Lymphoblastoid Cell Lines..” Msphere, vol. 2, no. 6, Nov. 2017. Pubmed, doi:10.1128/mSphere.00305-17.
PMID
29202043
Source
pubmed
Published In
Msphere
Volume
2
Issue
6
Publish Date
2017
DOI
10.1128/mSphere.00305-17

Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets.

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.

Authors
Bouska, A; Bi, C; Lone, W; Zhang, W; Kedwaii, A; Heavican, T; Lachel, CM; Yu, J; Ferro, R; Eldorghamy, N; Greiner, TC; Vose, J; Weisenburger, DD; Gascoyne, RD; Rosenwald, A; Ott, G; Campo, E; Rimsza, LM; Jaffe, ES; Braziel, RM; Siebert, R; Miles, RR; Dave, S; Reddy, A; Delabie, J; Staudt, LM; Song, JY; McKeithan, TW; Fu, K; Green, M; Chan, WC; Iqbal, J
MLA Citation
Bouska, Alyssa, et al. “Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets..” Blood, vol. 130, no. 16, Oct. 2017, pp. 1819–31. Pubmed, doi:10.1182/blood-2017-02-767335.
PMID
28801451
Source
pubmed
Published In
Blood
Volume
130
Issue
16
Publish Date
2017
Start Page
1819
End Page
1831
DOI
10.1182/blood-2017-02-767335

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Authors
Reddy, A; Zhang, J; Davis, NS; Moffitt, AB; Love, CL; Waldrop, A; Leppa, S; Pasanen, A; Meriranta, L; Karjalainen-Lindsberg, M-L; Nørgaard, P; Pedersen, M; Gang, AO; Høgdall, E; Heavican, TB; Lone, W; Iqbal, J; Qin, Q; Li, G; Kim, SY; Healy, J; Richards, KL; Fedoriw, Y; Bernal-Mizrachi, L; Koff, JL; Staton, AD; Flowers, CR; Paltiel, O; Goldschmidt, N; Calaminici, M; Clear, A; Gribben, J; Nguyen, E; Czader, MB; Ondrejka, SL; Collie, A; Hsi, ED; Tse, E; Au-Yeung, RKH; Kwong, Y-L; Srivastava, G; Choi, WWL; Evens, AM; Pilichowska, M; Sengar, M; Reddy, N; Li, S; Chadburn, A; Gordon, LI; Jaffe, ES; Levy, S; Rempel, R; Tzeng, T; Happ, LE; Dave, T; Rajagopalan, D; Datta, J; Dunson, DB; Dave, SS
MLA Citation
Reddy, Anupama, et al. “Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma..” Cell, vol. 171, no. 2, Oct. 2017, pp. 481-494.e15. Pubmed, doi:10.1016/j.cell.2017.09.027.
PMID
28985567
Source
pubmed
Published In
Cell
Volume
171
Issue
2
Publish Date
2017
Start Page
481
End Page
494.e15
DOI
10.1016/j.cell.2017.09.027

Origin of Non-Hodgkin Lymphoma

Authors
McKinney, MS; Dave, SS
MLA Citation
McKinney, M. S., and S. S. Dave. “Origin of Non-Hodgkin Lymphoma.” Hematology: Basic Principles and Practice, 2017, pp. 1230–43. Scopus, doi:10.1016/B978-0-323-35762-3.00076-7.
Source
scopus
Publish Date
2017
Start Page
1230
End Page
1243
DOI
10.1016/B978-0-323-35762-3.00076-7

Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

Authors
Guo, X; Koff, JL; Moffitt, AB; Cinar, M; Ramachandiran, S; Chen, Z; Switchenko, JM; Mosunjac, M; Neill, SG; Mann, KP; Bagirov, M; Du, Y; Natkunam, Y; Khoury, HJ; Rossi, MR; Harris, W; Flowers, CR; Lossos, IS; Boise, LH; Dave, SS; Kowalski, J; Bernal-Mizrachi, L
MLA Citation
Guo, X., et al. “Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype..” Oncogene, vol. 36, no. 29, July 2017, pp. 4224–32. Pubmed, doi:10.1038/onc.2017.90.
PMID
28368397
Source
pubmed
Published In
Oncogene
Volume
36
Issue
29
Publish Date
2017
Start Page
4224
End Page
4232
DOI
10.1038/onc.2017.90

Generation and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma.

Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be fully explored. Here we use CRISPR-Cas9 to generate multiple subtypes of primary sarcomas efficiently in wild type and genetically engineered mice. These data demonstrate that CRISPR-Cas9 can be used to generate multiple subtypes of soft tissue sarcomas in mice. Primary sarcomas generated with CRISPR-Cas9 and Cre recombinase technology had similar histology, growth kinetics, copy number variation and mutational load as assessed by whole exome sequencing. These results show that sarcomas generated with CRISPR-Cas9 technology are similar to sarcomas generated with conventional modelling techniques and suggest that CRISPR-Cas9 can be used to more rapidly generate genotypically and phenotypically similar cancers.

Authors
Huang, J; Chen, M; Whitley, MJ; Kuo, H-C; Xu, ES; Walens, A; Mowery, YM; Van Mater, D; Eward, WC; Cardona, DM; Luo, L; Ma, Y; Lopez, OM; Nelson, CE; Robinson-Hamm, JN; Reddy, A; Dave, SS; Gersbach, CA; Dodd, RD; Kirsch, DG
MLA Citation
Huang, Jianguo, et al. “Generation and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma..” Nat Commun, vol. 8, July 2017. Pubmed, doi:10.1038/ncomms15999.
PMID
28691711
Source
pubmed
Published In
Nature Communications
Volume
8
Publish Date
2017
Start Page
15999
DOI
10.1038/ncomms15999

Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models.

Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat graft-versus-host disease (GVHD) have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated MØs [MEMs]); however, their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison with MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated MØs: CD206 and CD163. RNA-Seq analysis of MEMs, as compared with MØs, show a distinct gene expression profile that positively correlates with multiple pathways important in tissue repair. MEMs also show increased expression of IL-6, transforming growth factor-β, arginase-1, CD73, and decreased expression of IL-12 and tumor necrosis factor-α. We show that IL-6 secretion is controlled in part by the cyclo-oxygenase-2, arginase, and JAK1/STAT1 pathway. When tested in vivo, we show that human MEMs significantly enhance survival from lethal GVHD and improve survival of mice from radiation injury. We show these effects could be mediated in part through suppression of human T cell proliferation and may have attenuated host tissue injury in part by enhancing murine fibroblast proliferation. MEMs are a unique MØ subset with therapeutic potential for the management of GVHD and/or protection from radiation-induced injury.

Authors
Bouchlaka, MN; Moffitt, AB; Kim, J; Kink, JA; Bloom, DD; Love, C; Dave, S; Hematti, P; Capitini, CM
MLA Citation
Bouchlaka, Myriam N., et al. “Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models..” Biol Blood Marrow Transplant, vol. 23, no. 6, June 2017, pp. 897–905. Pubmed, doi:10.1016/j.bbmt.2017.02.018.
PMID
28257800
Source
pubmed
Published In
Biol Blood Marrow Transplant
Volume
23
Issue
6
Publish Date
2017
Start Page
897
End Page
905
DOI
10.1016/j.bbmt.2017.02.018

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

Authors
Moffitt, AB; Ondrejka, SL; McKinney, M; Rempel, RE; Goodlad, JR; Teh, CH; Leppa, S; Mannisto, S; Kovanen, PE; Tse, E; Au-Yeung, RKH; Kwong, Y-L; Srivastava, G; Iqbal, J; Yu, J; Naresh, K; Villa, D; Gascoyne, RD; Said, J; Czader, MB; Chadburn, A; Richards, KL; Rajagopalan, D; Davis, NS; Smith, EC; Palus, BC; Tzeng, TJ; Healy, JA; Lugar, PL; Datta, J; Love, C; Levy, S; Dunson, DB; Zhuang, Y; Hsi, ED; Dave, SS
MLA Citation
Moffitt, Andrea B., et al. “Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2..” J Exp Med, vol. 214, no. 5, May 2017, pp. 1371–86. Pubmed, doi:10.1084/jem.20160894.
PMID
28424246
Source
pubmed
Published In
J Exp Med
Volume
214
Issue
5
Publish Date
2017
Start Page
1371
End Page
1386
DOI
10.1084/jem.20160894

Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors.

Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development in Id2/Id3 double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared between Id2/Id3 double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.

Authors
Li, J; Roy, S; Kim, Y-M; Li, S; Zhang, B; Love, C; Reddy, A; Rajagopalan, D; Dave, S; Diehl, AM; Zhuang, Y
MLA Citation
Li, Jia, et al. “Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors..” J Immunol, vol. 198, no. 8, Apr. 2017, pp. 3136–48. Pubmed, doi:10.4049/jimmunol.1601935.
PMID
28258199
Source
pubmed
Published In
J Immunol
Volume
198
Issue
8
Publish Date
2017
Start Page
3136
End Page
3148
DOI
10.4049/jimmunol.1601935

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.

Authors
McKinney, M; Moffitt, AB; Gaulard, P; Travert, M; De Leval, L; Nicolae, A; Raffeld, M; Jaffe, ES; Pittaluga, S; Xi, L; Heavican, T; Iqbal, J; Belhadj, K; Delfau-Larue, MH; Fataccioli, V; Czader, MB; Lossos, IS; Chapman-Fredricks, JR; Richards, KL; Fedoriw, Y; Ondrejka, SL; Hsi, ED; Low, L; Weisenburger, D; Chan, WC; Mehta-Shah, N; Horwitz, S; Bernal-Mizrachi, L; Flowers, CR; Beaven, AW; Parihar, M; Baseggio, L; Parrens, M; Moreau, A; Sujobert, P; Pilichowska, M; Evens, AM; Chadburn, A; Au-Yeung, RKH; Srivastava, G; Choi, WWL; Goodlad, JR; Aurer, I; Basic-Kinda, S; Gascoyne, RD; Davis, NS; Li, G; Zhang, J; Rajagopalan, D; Reddy, A; Love, C; Levy, S; Zhuang, Y; Datta, J; Dunson, DB; Davé, SS
MLA Citation
McKinney, Matthew, et al. “The Genetic Basis of Hepatosplenic T-cell Lymphoma..” Cancer Discov, vol. 7, no. 4, Apr. 2017, pp. 369–79. Pubmed, doi:10.1158/2159-8290.CD-16-0330.
PMID
28122867
Source
pubmed
Published In
Cancer Discov
Volume
7
Issue
4
Publish Date
2017
Start Page
369
End Page
379
DOI
10.1158/2159-8290.CD-16-0330

Clinical Applications of the Genomic Landscape of Aggressive Non-Hodgkin Lymphoma.

In this review, we examine the genomic landscapes of lymphomas that arise from B, T, and natural killer cells. Lymphomas represent a striking spectrum of clinical behaviors. Although some lymphomas are curable with standard therapy, the majority of the affected patients succumb to their disease. Here, the genetic underpinnings of these heterogeneous entities are reviewed. We consider B-cell lymphomas, including Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, and primary mediastinal B-cell lymphoma. We also examine T-cell lymphomas, including anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma, and other peripheral T-cell lymphomas. Together, these malignancies make up most lymphomas diagnosed around the world. Genomic technologies, including microarrays and next-generation sequencing, have enabled a better understanding of the molecular underpinnings of these cancers. We describe the broad genomics findings that characterize these lymphoma types and discuss new therapeutic opportunities that arise from these findings.

Authors
Moffitt, AB; Dave, SS
MLA Citation
Moffitt, Andrea B., and Sandeep S. Dave. “Clinical Applications of the Genomic Landscape of Aggressive Non-Hodgkin Lymphoma..” J Clin Oncol, vol. 35, no. 9, Mar. 2017, pp. 955–62. Pubmed, doi:10.1200/JCO.2016.71.7603.
PMID
28297626
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
35
Issue
9
Publish Date
2017
Start Page
955
End Page
962
DOI
10.1200/JCO.2016.71.7603

GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo.

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.

Authors
Healy, JA; Nugent, A; Rempel, RE; Moffitt, AB; Davis, NS; Jiang, X; Shingleton, JR; Zhang, J; Love, C; Datta, J; McKinney, ME; Tzeng, TJ; Wettschureck, N; Offermanns, S; Walzer, KA; Chi, J-T; Rasheed, SAK; Casey, PJ; Lossos, IS; Dave, SS
MLA Citation
Healy, Jane A., et al. “GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo..” Blood, vol. 127, no. 22, June 2016, pp. 2723–31. Pubmed, doi:10.1182/blood-2015-07-659938.
PMID
26989201
Source
pubmed
Published In
Blood
Volume
127
Issue
22
Publish Date
2016
Start Page
2723
End Page
2731
DOI
10.1182/blood-2015-07-659938

A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes.

BACKGROUND: Human erythrocytes are terminally differentiated, anucleate cells long thought to lack RNAs. However, previous studies have shown the persistence of many small-sized RNAs in erythrocytes. To comprehensively define the erythrocyte transcriptome, we used high-throughput sequencing to identify both short (18-24 nt) and long (>200 nt) RNAs in mature erythrocytes. RESULTS: Analysis of the short RNA transcriptome with miRDeep identified 287 known and 72 putative novel microRNAs. Unexpectedly, we also uncover an extensive repertoire of long erythrocyte RNAs that encode many proteins critical for erythrocyte differentiation and function. Additionally, the erythrocyte long RNA transcriptome is significantly enriched in the erythroid progenitor transcriptome. Joint analysis of both short and long RNAs identified several loci with co-expression of both microRNAs and long RNAs spanning microRNA precursor regions. Within the miR-144/451 locus previously implicated in erythroid development, we observed unique co-expression of several primate-specific noncoding RNAs, including a lncRNA, and miR-4732-5p/-3p. We show that miR-4732-3p targets both SMAD2 and SMAD4, two critical components of the TGF-β pathway implicated in erythropoiesis. Furthermore, miR-4732-3p represses SMAD2/4-dependent TGF-β signaling, thereby promoting cell proliferation during erythroid differentiation. CONCLUSIONS: Our study presents the most extensive profiling of erythrocyte RNAs to date, and describes primate-specific interactions between the key modulator miR-4732-3p and TGF-β signaling during human erythropoiesis.

Authors
Doss, JF; Corcoran, DL; Jima, DD; Telen, MJ; Dave, SS; Chi, J-T
MLA Citation
Doss, Jennifer F., et al. “A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes..” Bmc Genomics, vol. 16, Nov. 2015. Pubmed, doi:10.1186/s12864-015-2156-2.
PMID
26573221
Source
pubmed
Published In
Bmc Genomics
Volume
16
Publish Date
2015
Start Page
952
DOI
10.1186/s12864-015-2156-2

SMRT Sequencing for Parallel Analysis of Multiple Targets and Accurate SNP Phasing.

Single-molecule real-time (SMRT) sequencing generates much longer reads than other widely used next-generation (next-gen) sequencing methods, but its application to whole genome/exome analysis has been limited. Here, we describe the use of SMRT sequencing coupled with barcoding to simultaneously analyze one or a small number of genomic targets derived from multiple sources. In the budding yeast system, SMRT sequencing was used to analyze strand-exchange intermediates generated during mitotic recombination and to analyze genetic changes in a forward mutation assay. The general barcoding-SMRT approach was then extended to diffuse large B-cell lymphoma primary tumors and cell lines, where detected changes agreed with prior Illumina exome sequencing. A distinct advantage afforded by SMRT sequencing over other next-gen methods is that it immediately provides the linkage relationships between SNPs in the target segment sequenced. The strength of our approach for mutation/recombination studies (as well as linkage identification) derives from its inherent computational simplicity coupled with a lack of reliance on sophisticated statistical analyses.

Authors
Guo, X; Lehner, K; O'Connell, K; Zhang, J; Dave, SS; Jinks-Robertson, S
MLA Citation
Guo, Xiaoge, et al. “SMRT Sequencing for Parallel Analysis of Multiple Targets and Accurate SNP Phasing..” G3 (Bethesda), vol. 5, no. 12, Oct. 2015, pp. 2801–08. Pubmed, doi:10.1534/g3.115.023317.
PMID
26497143
Source
pubmed
Published In
G3 (Bethesda, Md.)
Volume
5
Issue
12
Publish Date
2015
Start Page
2801
End Page
2808
DOI
10.1534/g3.115.023317

The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma.

Epstein-Barr virus (EBV) infection is a common feature of B cell lymphoproliferative disorders (LPDs), including diffuse large B cell lymphoma. Approximately 10 % of DLBCLs are EBV-positive, with the highest incidence in immunocompromised and elderly patients. Here, we review the clinical, genetic, and pathologic characteristics of DLBCL and discuss the molecular role of EBV in lymphoma tumorigenesis. Using EBV-positive DLBCL of the elderly as a model, we describe the key features of EBV-positive DLBCL. Studies of EBV-positive DLBCL of the elderly demonstrate that EBV-positive DLBCL has a distinct biology, related to both viral and host factors. The pathogenic mechanisms noted in EBV-positive DLBCL of the elderly, including enhanced NFκB activity, are likely to be a generalizable feature of EBV-positive DLBCL. Therefore, we review how this information might be used to target the EBV or its host response for the development of novel treatment strategies.

Authors
Healy, JA; Dave, SS
MLA Citation
Healy, Jane A., and Sandeep S. Dave. “The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma..” Curr Top Microbiol Immunol, vol. 390, no. Pt 1, 2015, pp. 315–37. Pubmed, doi:10.1007/978-3-319-22822-8_13.
PMID
26424652
Source
pubmed
Published In
Current Topics in Microbiology and Immunology
Volume
390
Issue
Pt 1
Publish Date
2015
Start Page
315
End Page
337
DOI
10.1007/978-3-319-22822-8_13

Molecular subtype classification of formalin-fixed, paraffin-embedded diffuse large B-cell lymphoma samples on the ICEPlex® system.

Authors
Collie, AMB; Nölling, J; Divakar, KM; Lin, JJ; Carver, P; Durkin, LM; Hill, BT; Smith, MR; Radivoyevitch, T; Kong, LI; Daly, T; Murugesan, G; Guenther-Johnson, J; Dave, SS; Manilich, EA; Hsi, ED
MLA Citation
Collie, Angela M. B., et al. “Molecular subtype classification of formalin-fixed, paraffin-embedded diffuse large B-cell lymphoma samples on the ICEPlex® system..” Br J Haematol, vol. 167, no. 2, Oct. 2014, pp. 281–85. Pubmed, doi:10.1111/bjh.12983.
PMID
24961756
Source
pubmed
Published In
Br J Haematol
Volume
167
Issue
2
Publish Date
2014
Start Page
281
End Page
285
DOI
10.1111/bjh.12983

New clues to the molecular pathogenesis of Burkitt lymphoma revealed through next-generation sequencing.

PURPOSE OF REVIEW: Burkitt lymphoma is an important clinical and model disease arising from B cells. Burkitt lymphoma is characterized by translocation of the c-MYC gene to an immunoglobulin enhancer region, resulting in enhanced cell proliferation and rapid tumor progression. The development of deep sequencing has widened the scope of genetic analysis to reveal the role of additional collaborating mutations in Burkitt lymphoma. In this review, we examine the role of additional genetic events that cooperate with MYC in Burkitt lymphoma pathogenesis. RECENT FINDINGS: Next-generation sequencing of Burkitt lymphoma has identified recurrent silencing mutations in ID3, a novel tumor suppressor gene. In addition, mutations in a number of genes including GNA13, TP53, and SMARCA4 occur in Burkitt lymphoma. Copy number status has implicated recurrent aberrations including gains of 1q and 18q and deletion of 19p13. Additionally, microRNA and gene expression profiling has revealed unique transcriptome signatures in Burkitt lymphoma subgroups. SUMMARY: Analysis of genetic alterations in Burkitt lymphoma has yielded a better understanding of the pathogenesis of this disease. These observations could lead to more effective strategies for the diagnosis and treatment of Burkitt lymphoma.

Authors
Greenough, A; Dave, SS
MLA Citation
Greenough, Adrienne, and Sandeep S. Dave. “New clues to the molecular pathogenesis of Burkitt lymphoma revealed through next-generation sequencing..” Curr Opin Hematol, vol. 21, no. 4, July 2014, pp. 326–32. Pubmed, doi:10.1097/MOH.0000000000000059.
PMID
24867287
Source
pubmed
Published In
Curr Opin Hematol
Volume
21
Issue
4
Publish Date
2014
Start Page
326
End Page
332
DOI
10.1097/MOH.0000000000000059

Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

BACKGROUND: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. METHODS: We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. RESULTS: We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. CONCLUSIONS: Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).

Authors
Woyach, JA; Furman, RR; Liu, T-M; Ozer, HG; Zapatka, M; Ruppert, AS; Xue, L; Li, DH-H; Steggerda, SM; Versele, M; Dave, SS; Zhang, J; Yilmaz, AS; Jaglowski, SM; Blum, KA; Lozanski, A; Lozanski, G; James, DF; Barrientos, JC; Lichter, P; Stilgenbauer, S; Buggy, JJ; Chang, BY; Johnson, AJ; Byrd, JC
MLA Citation
Woyach, Jennifer A., et al. “Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib..” N Engl J Med, vol. 370, no. 24, June 2014, pp. 2286–94. Pubmed, doi:10.1056/NEJMoa1400029.
PMID
24869598
Source
pubmed
Published In
The New England Journal of Medicine
Volume
370
Issue
24
Publish Date
2014
Start Page
2286
End Page
2294
DOI
10.1056/NEJMoa1400029

The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.

In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.

Authors
Zhang, J; Jima, D; Moffitt, AB; Liu, Q; Czader, M; Hsi, ED; Fedoriw, Y; Dunphy, CH; Richards, KL; Gill, JI; Sun, Z; Love, C; Scotland, P; Lock, E; Levy, S; Hsu, DS; Dunson, D; Dave, SS
MLA Citation
Zhang, Jenny, et al. “The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells..” Blood, vol. 123, no. 19, May 2014, pp. 2988–96. Pubmed, doi:10.1182/blood-2013-07-517177.
PMID
24682267
Source
pubmed
Published In
Blood
Volume
123
Issue
19
Publish Date
2014
Start Page
2988
End Page
2996
DOI
10.1182/blood-2013-07-517177

The polyphony of BACH2.

Authors
Dave, SS
MLA Citation
Dave, Sandeep S. “The polyphony of BACH2..” Blood, vol. 123, no. 7, Feb. 2014. Pubmed, doi:10.1182/blood-2014-01-542449.
PMID
24526774
Source
pubmed
Published In
Blood
Volume
123
Issue
7
Publish Date
2014
Start Page
950
DOI
10.1182/blood-2014-01-542449

Merkel cell carcinoma with partial B-cell blastic immunophenotype: a potential mimic of cutaneous richter transformation in a patient with chronic lymphocytic lymphoma.

Merkel cell polyomavirus (MCPyV) is a DNA virus whose pathogenic mechanisms in Merkel cell carcinoma (MCC) are still being unraveled. Emerging reports of an association between MCPyV and chronic lymphocytic lymphoma (CLL) have begun to broaden our understanding of the oncogenic mechanisms of this virus and the known association between these 2 malignancies. Herein, we report a case of MCC demonstrating a B-cell immunophenotype arising in a patient with CLL being treated with rituximab. In this context, we discuss the differential diagnostic considerations, especially with cutaneous Richter transformation (diffuse large B-cell lymphoma). We also assessed for the presence of MCPyV in both the patient's MCC and the CLL. Finally, we provide a large meta-analysis of patients with CLL and MCC. Patients with both MCC and CLL have a dismal prognosis, with greater than 50% overall mortality within the first year and a half after MCC diagnosis.

Authors
Papalas, JA; McKinney, MS; Kulbacki, E; Dave, SS; Wang, E
MLA Citation
Papalas, John A., et al. “Merkel cell carcinoma with partial B-cell blastic immunophenotype: a potential mimic of cutaneous richter transformation in a patient with chronic lymphocytic lymphoma..” Am J Dermatopathol, vol. 36, no. 2, Feb. 2014, pp. 148–52. Pubmed, doi:10.1097/DAD.0b013e31829ed784.
PMID
24556900
Source
pubmed
Published In
The American Journal of Dermatopathology
Volume
36
Issue
2
Publish Date
2014
Start Page
148
End Page
152
DOI
10.1097/DAD.0b013e31829ed784

Lymphomas

Authors
Dave, S; Walsh, K
MLA Citation
Dave, S., and K. Walsh. Lymphomas. Vol. 2, Aug. 2013, pp. 668–74. Scopus, doi:10.1016/B978-0-12-382227-7.00057-4.
Source
scopus
Volume
2
Publish Date
2013
Start Page
668
End Page
674
DOI
10.1016/B978-0-12-382227-7.00057-4

Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and fewer than half of patients are cured with standard first-line therapy. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL, one of the most common cancers in veterinary oncology, is morphologically similar to hDLBCL and is treated using similar chemotherapeutic protocols. With genomic technologies, it is now possible to molecularly evaluate dogs as a potential large-animal model for hDLBCL. We evaluated canine B-cell lymphomas (cBCL) using immunohistochemistry (IHC) and gene expression profiling. cBCL expression profiles were similar in many ways to hDLBCLs. For instance, a subset had increased expression of NF-κB pathway genes, mirroring human activated B-cell (ABC)-type DLBCL. Furthermore, immunoglobulin heavy chain ongoing mutation status, which is correlated with ABC/germinal center B-cell cell of origin in hDLBCL, separated cBCL into two groups with statistically different progression-free and overall survival times. In contrast with hDLBCL, cBCL rarely expressed BCL6 and MUM1/IRF4 by IHC. Collectively, these studies identify molecular similarities to hDLBCL that introduce pet dogs as a representative model of hDLBCL for future studies, including therapeutic clinical trials.

Authors
Richards, KL; Motsinger-Reif, AA; Chen, H-W; Fedoriw, Y; Fan, C; Nielsen, DM; Small, GW; Thomas, R; Smith, C; Dave, SS; Perou, CM; Breen, M; Borst, LB; Suter, SE
MLA Citation
Richards, Kristy L., et al. “Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL..” Cancer Res, vol. 73, no. 16, Aug. 2013, pp. 5029–39. Pubmed, doi:10.1158/0008-5472.CAN-12-3546.
PMID
23783577
Source
pubmed
Published In
Cancer Res
Volume
73
Issue
16
Publish Date
2013
Start Page
5029
End Page
5039
DOI
10.1158/0008-5472.CAN-12-3546

PAK1 mediates resistance to PI3K inhibition in lymphomas.

PURPOSE: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas. EXPERIMENTAL DESIGN: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs. RESULTS: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition. CONCLUSION: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

Authors
Walsh, K; McKinney, MS; Love, C; Liu, Q; Fan, A; Patel, A; Smith, J; Beaven, A; Jima, DD; Dave, SS
MLA Citation
Walsh, Katherine, et al. “PAK1 mediates resistance to PI3K inhibition in lymphomas..” Clin Cancer Res, vol. 19, no. 5, Mar. 2013, pp. 1106–15. Pubmed, doi:10.1158/1078-0432.CCR-12-1060.
PMID
23300274
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
19
Issue
5
Publish Date
2013
Start Page
1106
End Page
1115
DOI
10.1158/1078-0432.CCR-12-1060

Biomimetic, synthetic HDL nanostructures for lymphoma.

New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation.

Authors
Yang, S; Damiano, MG; Zhang, H; Tripathy, S; Luthi, AJ; Rink, JS; Ugolkov, AV; Singh, ATK; Dave, SS; Gordon, LI; Thaxton, CS
MLA Citation
Yang, Shuo, et al. “Biomimetic, synthetic HDL nanostructures for lymphoma..” Proc Natl Acad Sci U S A, vol. 110, no. 7, Feb. 2013, pp. 2511–16. Pubmed, doi:10.1073/pnas.1213657110.
PMID
23345442
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
110
Issue
7
Publish Date
2013
Start Page
2511
End Page
2516
DOI
10.1073/pnas.1213657110

Genetic heterogeneity of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.

Authors
Zhang, J; Grubor, V; Love, CL; Banerjee, A; Richards, KL; Mieczkowski, PA; Dunphy, C; Choi, W; Au, WY; Srivastava, G; Lugar, PL; Rizzieri, DA; Lagoo, AS; Bernal-Mizrachi, L; Mann, KP; Flowers, C; Naresh, K; Evens, A; Gordon, LI; Czader, M; Gill, JI; Hsi, ED; Liu, Q; Fan, A; Walsh, K; Jima, D; Smith, LL; Johnson, AJ; Byrd, JC; Luftig, MA; Ni, T; Zhu, J; Chadburn, A; Levy, S; Dunson, D; Dave, SS
MLA Citation
Zhang, Jenny, et al. “Genetic heterogeneity of diffuse large B-cell lymphoma..” Proc Natl Acad Sci U S A, vol. 110, no. 4, Jan. 2013, pp. 1398–403. Pubmed, doi:10.1073/pnas.1205299110.
PMID
23292937
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
110
Issue
4
Publish Date
2013
Start Page
1398
End Page
1403
DOI
10.1073/pnas.1205299110

Genomic stratification for the treatment of lymphomas.

The application of high-throughput genomic approaches in lymphomas has generated a wealth of data regarding the molecular underpinnings of these cancers. In this review, key findings from recent studies are discussed, as well as the genetic heterogeneity that underlies common lymphomas including diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia, and the implications for identifying new therapeutic opportunities and personalized medicine.

Authors
Dave, SS
MLA Citation
Dave, Sandeep S. “Genomic stratification for the treatment of lymphomas..” Hematology Am Soc Hematol Educ Program, vol. 2013, 2013, pp. 331–34. Pubmed, doi:10.1182/asheducation-2013.1.331.
PMID
24319200
Source
pubmed
Published In
Hematology Am Soc Hematol Educ Program
Volume
2013
Publish Date
2013
Start Page
331
End Page
334
DOI
10.1182/asheducation-2013.1.331

MicroRNA expression profiling using microarrays.

MicroRNAs are small noncoding RNAs which are able to regulate gene expression at both the transcriptional and translational levels. There is a growing recognition of the role of microRNAs in nearly every tissue type and cellular process. Thus there is an increasing need for accurate quantitation of microRNA expression in a variety of tissues. Microarrays provide a robust method for the examination of microRNA expression. In this chapter, we describe detailed methods for the use of microarrays to measure microRNA expression and discuss methods for the analysis of microRNA expression data.

Authors
Love, C; Dave, S
MLA Citation
Love, Cassandra, and Sandeep Dave. “MicroRNA expression profiling using microarrays..” Methods Mol Biol, vol. 999, 2013, pp. 285–96. Pubmed, doi:10.1007/978-1-62703-357-2_21.
PMID
23666707
Source
pubmed
Published In
Methods Mol Biol
Volume
999
Publish Date
2013
Start Page
285
End Page
296
DOI
10.1007/978-1-62703-357-2_21

The genetic landscape of mutations in Burkitt lymphoma.

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.

Authors
Love, C; Sun, Z; Jima, D; Li, G; Zhang, J; Miles, R; Richards, KL; Dunphy, CH; Choi, WWL; Srivastava, G; Lugar, PL; Rizzieri, DA; Lagoo, AS; Bernal-Mizrachi, L; Mann, KP; Flowers, CR; Naresh, KN; Evens, AM; Chadburn, A; Gordon, LI; Czader, MB; Gill, JI; Hsi, ED; Greenough, A; Moffitt, AB; McKinney, M; Banerjee, A; Grubor, V; Levy, S; Dunson, DB; Dave, SS
MLA Citation
Love, Cassandra, et al. “The genetic landscape of mutations in Burkitt lymphoma..” Nat Genet, vol. 44, no. 12, Dec. 2012, pp. 1321–25. Pubmed, doi:10.1038/ng.2468.
PMID
23143597
Source
pubmed
Published In
Nat Genet
Volume
44
Issue
12
Publish Date
2012
Start Page
1321
End Page
1325
DOI
10.1038/ng.2468

Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation.

Epstein-Barr virus (EBV) is an oncogenic human herpesvirus that dramatically reorganizes host gene expression to immortalize primary B cells. In this study, we analyzed EBV-regulated host gene expression changes following primary B-cell infection, both during initial proliferation and through transformation into lymphoblastoid cell lines (LCLs). While most EBV-regulated mRNAs were changed during the transition from resting, uninfected B cells through initial B-cell proliferation, a substantial number of mRNAs changed uniquely from early proliferation through LCL outgrowth. We identified constitutively and dynamically EBV-regulated biological processes, protein classes, and targets of specific transcription factors. Early after infection, genes associated with proliferation, stress responses, and the p53 pathway were highly enriched. However, the transition from early to long-term outgrowth was characterized by genes involved in the inhibition of apoptosis, the actin cytoskeleton, and NF-κB activity. It was previously thought that the major viral protein responsible for NF-κB activation, latent membrane protein 1 (LMP1), is expressed within 2 days after infection. Our data indicate that while this is true, LCL-level LMP1 expression and NF-κB activity are not evident until 3 weeks after primary B-cell infection. Furthermore, heterologous NF-κB activation during the first week after infection increased the transformation efficiency, while early NF-κB inhibition had no effect on transformation. Rather, inhibition of NF-κB was not toxic to EBV-infected cells until LMP1 levels and NF-κB activity were high. These data collectively highlight the dynamic nature of EBV-regulated host gene expression and support the notion that early EBV-infected proliferating B cells have a fundamentally distinct growth and survival phenotype from that of LCLs.

Authors
Price, AM; Tourigny, JP; Forte, E; Salinas, RE; Dave, SS; Luftig, MA
MLA Citation
Price, Alexander M., et al. “Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation..” J Virol, vol. 86, no. 20, Oct. 2012, pp. 11096–106. Pubmed, doi:10.1128/JVI.01069-12.
PMID
22855490
Source
pubmed
Published In
J Virol
Volume
86
Issue
20
Publish Date
2012
Start Page
11096
End Page
11106
DOI
10.1128/JVI.01069-12

The Epstein-Barr virus (EBV)-induced tumor suppressor microRNA MiR-34a is growth promoting in EBV-infected B cells.

Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-κB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic-virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts.

Authors
Forte, E; Salinas, RE; Chang, C; Zhou, T; Linnstaedt, SD; Gottwein, E; Jacobs, C; Jima, D; Li, Q-J; Dave, SS; Luftig, MA
MLA Citation
Forte, Eleonora, et al. “The Epstein-Barr virus (EBV)-induced tumor suppressor microRNA MiR-34a is growth promoting in EBV-infected B cells..” J Virol, vol. 86, no. 12, June 2012, pp. 6889–98. Pubmed, doi:10.1128/JVI.07056-11.
PMID
22496226
Source
pubmed
Published In
J Virol
Volume
86
Issue
12
Publish Date
2012
Start Page
6889
End Page
6898
DOI
10.1128/JVI.07056-11

Burkitt lymphoma: analysis of the genome.

Authors
Dave, S
MLA Citation
Dave, Sandeep. “Burkitt lymphoma: analysis of the genome..” Clin Adv Hematol Oncol, vol. 10, no. 1, Jan. 2012, pp. 54–55.
PMID
22398809
Source
pubmed
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
10
Issue
1
Publish Date
2012
Start Page
54
End Page
55

Molecular characterization of circulating plasma cells in patients with active systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a generalized autoimmune disease characterized by abnormal B cell activation and the occurrence of increased frequencies of circulating plasma cells (PC). The molecular characteristics and nature of circulating PC and B cells in SLE have not been completely characterized. Microarray analysis of gene expression was used to characterize circulating PC in subjects with active SLE. Flow cytometry was used to sort PC and comparator B cell populations from active SLE blood, normal blood and normal tonsil. The gene expression profiles of the sorted B cell populations were then compared. SLE PC exhibited a similar gene expression signature as tonsil PC. The differences in gene expression between SLE PC and normal tonsil PC and tonsil plasmablasts (PB) suggest a mature Ig secreting cell phenotype in the former population. Despite this, SLE PC differed in expression of about half the genes from previously published gene expression profiles of normal bone marrow PC, indicating that these cells had not achieved a fully mature status. Abnormal expression of several genes, including CXCR4 and S1P(1), suggests a mechanism for the persistence of SLE PC in the circulation. All SLE B cell populations revealed an interferon (IFN) gene signature previously only reported in unseparated SLE peripheral blood mononuclear cells. These data indicate that SLE PC are a unique population of Ig secreting cells with a gene expression profile indicative of a mature, but not fully differentiated phenotype.

Authors
Lugar, PL; Love, C; Grammer, AC; Dave, SS; Lipsky, PE
MLA Citation
Lugar, Patricia L., et al. “Molecular characterization of circulating plasma cells in patients with active systemic lupus erythematosus..” Plos One, vol. 7, no. 9, 2012. Pubmed, doi:10.1371/journal.pone.0044362.
PMID
23028528
Source
pubmed
Published In
Plos One
Volume
7
Issue
9
Publish Date
2012
Start Page
e44362
DOI
10.1371/journal.pone.0044362

Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines.

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in latency and lymphomagenesis. Using PAR-CLIP, a technology which allows the direct and transcriptome-wide identification of miRNA targets, we delineate the target sites for all viral and cellular miRNAs expressed in PEL cell lines. The resulting data set revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs, including many involved in pathways relevant to KSHV pathogenesis. Moreover, 58% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of cellular miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, this study identifies an extensive list of KSHV miRNA targets, which are likely to influence viral replication and pathogenesis.

Authors
Gottwein, E; Corcoran, DL; Mukherjee, N; Skalsky, RL; Hafner, M; Nusbaum, JD; Shamulailatpam, P; Love, CL; Dave, SS; Tuschl, T; Ohler, U; Cullen, BR
MLA Citation
Gottwein, Eva, et al. “Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines..” Cell Host Microbe, vol. 10, no. 5, Nov. 2011, pp. 515–26. Pubmed, doi:10.1016/j.chom.2011.09.012.
PMID
22100165
Source
pubmed
Published In
Cell Host Microbe
Volume
10
Issue
5
Publish Date
2011
Start Page
515
End Page
526
DOI
10.1016/j.chom.2011.09.012

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Authors
Lanasa, MC; Allgood, SD; Slager, SL; Dave, SS; Love, C; Marti, GE; Kay, NE; Hanson, CA; Rabe, KG; Achenbach, SJ; Goldin, LR; Camp, NJ; Goodman, BK; Vachon, CM; Spector, LG; Rassenti, LZ; Leis, JF; Gockerman, JP; Strom, SS; Call, TG; Glenn, M; Cerhan, JR; Levesque, MC; Weinberg, JB; Caporaso, NE
MLA Citation
Lanasa, M. C., et al. “Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL..” Leukemia, vol. 25, no. 9, Sept. 2011, pp. 1459–66. Pubmed, doi:10.1038/leu.2011.117.
PMID
21617698
Source
pubmed
Published In
Leukemia
Volume
25
Issue
9
Publish Date
2011
Start Page
1459
End Page
1466
DOI
10.1038/leu.2011.117

HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.

HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers.

Authors
Hartman, ZC; Yang, X-Y; Glass, O; Lei, G; Osada, T; Dave, SS; Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Hartman, Zachary C., et al. “HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis..” Cancer Res, vol. 71, no. 13, July 2011, pp. 4380–91. Pubmed, doi:10.1158/0008-5472.CAN-11-0308.
PMID
21518778
Source
pubmed
Published In
Cancer Res
Volume
71
Issue
13
Publish Date
2011
Start Page
4380
End Page
4391
DOI
10.1158/0008-5472.CAN-11-0308

Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component.

The normal counterparts of mantle cell lymphoma (MCL) are naive, quiescent B cells that have not been processed through the germinal center (GC). For this reason, although lymphomas arising from GC or post-GC B cells often exhibit plasmacytic differentiation, MCL rarely presents with plasmacytic features. Seven cases of MCL with a monotypic plasma cell (PC) population were collected from 6 centers and were studied by immunohistochemistry, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms analysis, capillary gel electrophoresis, and restriction fragment length polymorphism of immunoglobulin heavy chain analysis of microdissections of each of the MCL and PC populations to assess their clonal relationship. The clinical presentation was rather unusual compared with typical MCL, with 2 cases arising from the extranodal soft tissues of the head. All MCL cases were morphologically and immunohistochemically typical, bearing the t(11;14)(q13;q32). In all cases, the PC population was clonal. In 5 of the 7 cases, the MCL and PC clones showed identical restriction fragments, indicating a common clonal origin of the neoplastic population. The 2 cases with clonal diversity denoted the coexistence of 2 different tumors in a composite lymphoma/PC neoplasm. Our findings suggest that MCL can present with a PC component that is often clonally related to the lymphoma, representing a rare but unique biological variant of this tumor.

Authors
Visco, C; Hoeller, S; Malik, JT; Xu-Monette, ZY; Wiggins, ML; Liu, J; Sanger, WG; Liu, Z; Chang, J; Ranheim, EA; Gradowski, JF; Serrano, S; Wang, H-Y; Liu, Q; Dave, S; Olsen, B; Gascoyne, RD; Campo, E; Swerdlow, SH; Chan, WC; Tzankov, A; Young, KH
MLA Citation
Visco, Carlo, et al. “Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component..” Am J Surg Pathol, vol. 35, no. 2, Feb. 2011, pp. 177–89. Pubmed, doi:10.1097/PAS.0b013e3182049a9c.
PMID
21263238
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
35
Issue
2
Publish Date
2011
Start Page
177
End Page
189
DOI
10.1097/PAS.0b013e3182049a9c

An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.

Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low, suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication, nor did the DDR marks colocalize with latent episomes. Rather, a transient period of EBV-induced hyperproliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoprotein EBNA3C was required to attenuate the EBV-induced DDR. We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization.

Authors
Nikitin, PA; Yan, CM; Forte, E; Bocedi, A; Tourigny, JP; White, RE; Allday, MJ; Patel, A; Dave, SS; Kim, W; Hu, K; Guo, J; Tainter, D; Rusyn, E; Luftig, MA
MLA Citation
Nikitin, Pavel A., et al. “An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells..” Cell Host Microbe, vol. 8, no. 6, Dec. 2010, pp. 510–22. Pubmed, doi:10.1016/j.chom.2010.11.004.
PMID
21147465
Source
pubmed
Published In
Cell Host Microbe
Volume
8
Issue
6
Publish Date
2010
Start Page
510
End Page
522
DOI
10.1016/j.chom.2010.11.004

Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs.

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-β pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.

Authors
Jima, DD; Zhang, J; Jacobs, C; Richards, KL; Dunphy, CH; Choi, WWL; Au, WY; Srivastava, G; Czader, MB; Rizzieri, DA; Lagoo, AS; Lugar, PL; Mann, KP; Flowers, CR; Bernal-Mizrachi, L; Naresh, KN; Evens, AM; Gordon, LI; Luftig, M; Friedman, DR; Weinberg, JB; Thompson, MA; Gill, JI; Liu, Q; How, T; Grubor, V; Gao, Y; Patel, A; Wu, H; Zhu, J; Blobe, GC; Lipsky, PE; Chadburn, A; Dave, SS; Hematologic Malignancies Research Consortium,
MLA Citation
Jima, Dereje D., et al. “Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs..” Blood, vol. 116, no. 23, Dec. 2010, pp. e118–27. Pubmed, doi:10.1182/blood-2010-05-285403.
PMID
20733160
Source
pubmed
Published In
Blood
Volume
116
Issue
23
Publish Date
2010
Start Page
e118
End Page
e127
DOI
10.1182/blood-2010-05-285403

Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling.

The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.

Authors
Hartmann, EM; Campo, E; Wright, G; Lenz, G; Salaverria, I; Jares, P; Xiao, W; Braziel, RM; Rimsza, LM; Chan, W-C; Weisenburger, DD; Delabie, J; Jaffe, ES; Gascoyne, RD; Dave, SS; Mueller-Hermelink, H-K; Staudt, LM; Ott, G; Beà, S; Rosenwald, A
MLA Citation
Hartmann, Elena M., et al. “Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling..” Blood, vol. 116, no. 6, Aug. 2010, pp. 953–61. Pubmed, doi:10.1182/blood-2010-01-263806.
PMID
20421449
Source
pubmed
Published In
Blood
Volume
116
Issue
6
Publish Date
2010
Start Page
953
End Page
961
DOI
10.1182/blood-2010-01-263806

Host factors for risk and survival in lymphoma.

All cancers arise from complex interactions between aspects of the patient (host) biology and the environment. Once tumors arise, they frequently remain dependent on interactions with their microenvironment for their growth and proliferation. In this review, we examine the contributions of the host genetics and environmental exposures to the development of lymphoma. We will further examine the interactions of the tumor and the microenvironment that influence tumor growth and proliferation.

Authors
Dave, SS
MLA Citation
Dave, Sandeep S. “Host factors for risk and survival in lymphoma..” Hematology Am Soc Hematol Educ Program, vol. 2010, 2010, pp. 255–58. Pubmed, doi:10.1182/asheducation-2010.1.255.
PMID
21239802
Source
pubmed
Published In
Hematology Am Soc Hematol Educ Program
Volume
2010
Publish Date
2010
Start Page
255
End Page
258
DOI
10.1182/asheducation-2010.1.255

SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype.

BACKGROUND: Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors. DESIGN AND METHODS: The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms. RESULTS: SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt's lymphoma but not in any other mature lymphoid neoplasm. SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt's lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma. CONCLUSIONS: SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma.

Authors
Mozos, A; Royo, C; Hartmann, E; De Jong, D; Baró, C; Valera, A; Fu, K; Weisenburger, DD; Delabie, J; Chuang, S-S; Jaffe, ES; Ruiz-Marcellan, C; Dave, S; Rimsza, L; Braziel, R; Gascoyne, RD; Solé, F; López-Guillermo, A; Colomer, D; Staudt, LM; Rosenwald, A; Ott, G; Jares, P; Campo, E
MLA Citation
Mozos, Ana, et al. “SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype..” Haematologica, vol. 94, no. 11, Nov. 2009, pp. 1555–62. Pubmed, doi:10.3324/haematol.2009.010264.
PMID
19880778
Source
pubmed
Published In
Haematologica
Volume
94
Issue
11
Publish Date
2009
Start Page
1555
End Page
1562
DOI
10.3324/haematol.2009.010264

Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma.

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-kappaB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-kappaB through blocking IkappaBalpha degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (10.8 vs 3.4 months; P = .003) in ABC compared with GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.ClinicalTrials.gov under identifier NCT00057902.

Authors
Dunleavy, K; Pittaluga, S; Czuczman, MS; Dave, SS; Wright, G; Grant, N; Shovlin, M; Jaffe, ES; Janik, JE; Staudt, LM; Wilson, WH
MLA Citation
Dunleavy, Kieron, et al. “Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma..” Blood, vol. 113, no. 24, June 2009, pp. 6069–76. Pubmed, doi:10.1182/blood-2009-01-199679.
PMID
19380866
Source
pubmed
Published In
Blood
Volume
113
Issue
24
Publish Date
2009
Start Page
6069
End Page
6076
DOI
10.1182/blood-2009-01-199679

Patterns of microRNA expression characterize stages of human B-cell differentiation.

Mature B-cell differentiation provides an important mechanism for the acquisition of adaptive immunity. Malignancies derived from mature B cells constitute the majority of leukemias and lymphomas. These malignancies often maintain the characteristics of the normal B cells that they are derived from, a feature that is frequently used in their diagnosis. The role of microRNAs in mature B cells is largely unknown. Through concomitant microRNA and mRNA profiling, we demonstrate a potential regulatory role for microRNAs at every stage of the mature B-cell differentiation process. In addition, we have experimentally identified a direct role for the microRNA regulation of key transcription factors in B-cell differentiation: LMO2 and PRDM1 (Blimp1). We also profiled the microRNA of B-cell tumors derived from diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia. We found that, in contrast to many other malignancies, common B-cell malignancies do not down-regulate microRNA expression. Although these tumors could be distinguished from each other with use of microRNA expression, each tumor type maintained the expression of the lineage-specific microRNAs. Expression of these lineage-specific microRNAs could correctly predict the lineage of B-cell malignancies in more than 95% of the cases. Thus, our data demonstrate that microRNAs may be important in maintaining the mature B-cell phenotype in normal and malignant B cells.

Authors
Zhang, J; Jima, DD; Jacobs, C; Fischer, R; Gottwein, E; Huang, G; Lugar, PL; Lagoo, AS; Rizzieri, DA; Friedman, DR; Weinberg, JB; Lipsky, PE; Dave, SS
MLA Citation
Zhang, Jenny, et al. “Patterns of microRNA expression characterize stages of human B-cell differentiation..” Blood, vol. 113, no. 19, May 2009, pp. 4586–94. Pubmed, doi:10.1182/blood-2008-09-178186.
PMID
19202128
Source
pubmed
Published In
Blood
Volume
113
Issue
19
Publish Date
2009
Start Page
4586
End Page
4594
DOI
10.1182/blood-2008-09-178186

Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.

Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.

Authors
Longo, NS; Lugar, PL; Yavuz, S; Zhang, W; Krijger, PHL; Russ, DE; Jima, DD; Dave, SS; Grammer, AC; Lipsky, PE
MLA Citation
Longo, Nancy S., et al. “Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting..” Blood, vol. 113, no. 16, Apr. 2009, pp. 3706–15. Pubmed, doi:10.1182/blood-2008-10-183632.
PMID
19023113
Source
pubmed
Published In
Blood
Volume
113
Issue
16
Publish Date
2009
Start Page
3706
End Page
3715
DOI
10.1182/blood-2008-10-183632

Stromal gene signatures in large-B-cell lymphomas.

BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Authors
Lenz, G; Wright, G; Dave, SS; Xiao, W; Powell, J; Zhao, H; Xu, W; Tan, B; Goldschmidt, N; Iqbal, J; Vose, J; Bast, M; Fu, K; Weisenburger, DD; Greiner, TC; Armitage, JO; Kyle, A; May, L; Gascoyne, RD; Connors, JM; Troen, G; Holte, H; Kvaloy, S; Dierickx, D; Verhoef, G; Delabie, J; Smeland, EB; Jares, P; Martinez, A; Lopez-Guillermo, A; Montserrat, E; Campo, E; Braziel, RM; Miller, TP; Rimsza, LM; Cook, JR; Pohlman, B; Sweetenham, J; Tubbs, RR; Fisher, RI; Hartmann, E; Rosenwald, A; Ott, G; Muller-Hermelink, H-K; Wrench, D; Lister, TA; Jaffe, ES; Wilson, WH; Chan, WC; Staudt, LM; Lymphoma/Leukemia Molecular Profiling Project,
MLA Citation
Lenz, G., et al. “Stromal gene signatures in large-B-cell lymphomas..” N Engl J Med, vol. 359, no. 22, Nov. 2008, pp. 2313–23. Pubmed, doi:10.1056/NEJMoa0802885.
PMID
19038878
Source
pubmed
Published In
The New England Journal of Medicine
Volume
359
Issue
22
Publish Date
2008
Start Page
2313
End Page
2323
DOI
10.1056/NEJMoa0802885

Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways.

Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.

Authors
Lenz, G; Wright, GW; Emre, NCT; Kohlhammer, H; Dave, SS; Davis, RE; Carty, S; Lam, LT; Shaffer, AL; Xiao, W; Powell, J; Rosenwald, A; Ott, G; Muller-Hermelink, HK; Gascoyne, RD; Connors, JM; Campo, E; Jaffe, ES; Delabie, J; Smeland, EB; Rimsza, LM; Fisher, RI; Weisenburger, DD; Chan, WC; Staudt, LM
MLA Citation
Lenz, Georg, et al. “Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways..” Proc Natl Acad Sci U S A, vol. 105, no. 36, Sept. 2008, pp. 13520–25. Pubmed, doi:10.1073/pnas.0804295105.
PMID
18765795
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
105
Issue
36
Publish Date
2008
Start Page
13520
End Page
13525
DOI
10.1073/pnas.0804295105

Chromosomal alterations detected by comparative genomic hybridization in subgroups of gene expression-defined Burkitt's lymphoma.

BACKGROUND: Burkitt's lymphoma is an aggressive B-cell lymphoma characterized by typical morphological, immunophenotypic and molecular features. Gene expression profiling provided a molecular signature of Burkitt's lymphoma, but also demonstrated that a subset of aggressive B-cell lymphomas not fulfilling the current World Health Organization criteria for the diagnosis of Burkitt's lymphoma nonetheless show a molecular signature of Burkitt's lymphoma ('discrepant Burkitt's lymphoma'). Given the different treatment of Burkitt's lymphoma and diffuse large B-cell lymphomas we investigated molecular differences within gene expression-defined Burkitt's lymphoma. DESIGN AND METHODS: We studied tumors from 51 Burkitt's lymphoma patients, comprising 26 with classic Burkitt's lymphoma, 17 with atypical Burkitt's lymphoma and 8 with 'discrepant Burkitt's lymphoma', by comparative genomic hybridization and gene expression profiling. RESULTS: Classic and atypical Burkitt's lymphoma (excluding 'discrepant Burkitt's lymphoma'), in adult and pediatric cases do not differ in underlying genomic imbalances or gene expression suggesting that these subgroups are molecularly homogeneous. 'Discrepant Burkitt's lymphoma', however, differ dramatically in the absolute number of alterations from classic/atypical Burkitt's lymphoma and from diffuse large B-cell lymphoma. Moreover, this category includes lymphomas that carry both the t(14;18) and t(8;14) translocations and are clinically characterized by presentation in adult patients and an aggressive course. CONCLUSIONS: Pediatric and adult Burkitt's lymphoma are molecularly homogeneous, whereas 'discrepant Burkitt's lymphoma' differ in underlying genetic and clinical features from typical/atypical Burkitt's lymphoma. 'Discrepant Burkitt's lymphoma' may therefore form a distinct genetic subgroup of aggressive B-cell lymphomas, which show poor response to multi-agent chemotherapy.

Authors
Salaverria, I; Zettl, A; Beà, S; Hartmann, EM; Dave, SS; Wright, GW; Boerma, E-J; Kluin, PM; Ott, G; Chan, WC; Weisenburger, DD; Lopez-Guillermo, A; Gascoyne, RD; Delabie, J; Rimsza, LM; Braziel, RM; Jaffe, ES; Staudt, LM; Müller-Hermelink, HK; Campo, E; Rosenwald, A; Leukemia and Lymphoma Molecular Profiling Project (LLMPP),
MLA Citation
Salaverria, Itziar, et al. “Chromosomal alterations detected by comparative genomic hybridization in subgroups of gene expression-defined Burkitt's lymphoma..” Haematologica, vol. 93, no. 9, Sept. 2008, pp. 1327–34. Pubmed, doi:10.3324/haematol.13071.
PMID
18698080
Source
pubmed
Published In
Haematologica
Volume
93
Issue
9
Publish Date
2008
Start Page
1327
End Page
1334
DOI
10.3324/haematol.13071

IRF4 addiction in multiple myeloma.

The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses. Current therapies for myeloma can extend survival but are not curative. Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome-wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.

Authors
Shaffer, AL; Emre, NCT; Lamy, L; Ngo, VN; Wright, G; Xiao, W; Powell, J; Dave, S; Yu, X; Zhao, H; Zeng, Y; Chen, B; Epstein, J; Staudt, LM
MLA Citation
Shaffer, Arthur L., et al. “IRF4 addiction in multiple myeloma..” Nature, vol. 454, no. 7201, July 2008, pp. 226–31. Pubmed, doi:10.1038/nature07064.
PMID
18568025
Source
pubmed
Published In
Nature
Volume
454
Issue
7201
Publish Date
2008
Start Page
226
End Page
231
DOI
10.1038/nature07064

Follicular lymphoma and the microenvironment.

Authors
Dave, SS
MLA Citation
Dave, Sandeep S. “Follicular lymphoma and the microenvironment..” Blood, vol. 111, no. 9, May 2008, pp. 4427–28. Pubmed, doi:10.1182/blood-2008-01-134643.
PMID
18441242
Source
pubmed
Published In
Blood
Volume
111
Issue
9
Publish Date
2008
Start Page
4427
End Page
4428
DOI
10.1182/blood-2008-01-134643

Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. In the least curable (ABC) subtype of DLBCL, survival of the malignant cells is dependent on constitutive activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway. In normal B cells, antigen receptor-induced NF-kappaB activation requires CARD11, a cytoplasmic scaffolding protein. To determine whether CARD11 contributes to tumorigenesis, we sequenced the CARD11 gene in human DLBCL tumors. We detected missense mutations in 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encoding the coiled-coil domain. Experimental introduction of CARD11 coiled-coil domain mutants into lymphoma cell lines resulted in constitutive NF-kappaB activation and enhanced NF-kappaB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogenein DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.

Authors
Lenz, G; Davis, RE; Ngo, VN; Lam, L; George, TC; Wright, GW; Dave, SS; Zhao, H; Xu, W; Rosenwald, A; Ott, G; Muller-Hermelink, HK; Gascoyne, RD; Connors, JM; Rimsza, LM; Campo, E; Jaffe, ES; Delabie, J; Smeland, EB; Fisher, RI; Chan, WC; Staudt, LM
MLA Citation
Lenz, Georg, et al. “Oncogenic CARD11 mutations in human diffuse large B cell lymphoma..” Science, vol. 319, no. 5870, Mar. 2008, pp. 1676–79. Pubmed, doi:10.1126/science.1153629.
PMID
18323416
Source
pubmed
Published In
Science
Volume
319
Issue
5870
Publish Date
2008
Start Page
1676
End Page
1679
DOI
10.1126/science.1153629

In reply [2]

Authors
Cuadros, M; Honrado, E; Zajac, M; Benitez, J; Martinez-Delgado, B; Dave, SS; Staudt, LM; Jaffe, ES; Milne, R; Alves, J; Rodríguez, J
MLA Citation
Cuadros, M., et al. “In reply [2].” Journal of Clinical Oncology, vol. 25, no. 30, Oct. 2007, pp. 4851–52. Scopus, doi:10.1200/JCO.2007.13.4858.
Source
scopus
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4851
End Page
4852
DOI
10.1200/JCO.2007.13.4858

Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas.

PURPOSE: Nodal peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous group of neoplasms, suggesting the existence of molecular differences contributing to their histologic and clinical variability. Initial expression profiling studies of T-cell lymphomas have been inconclusive in yielding clinically relevant insights. We applied DNA microarrays to gain insight into the molecular signatures associated with prognosis. MATERIALS AND METHODS: We analyzed the expression profiles of 35 nodal PTCLs (23 PTCLs unspecified and 12 angioimmunoblastic) using two different microarray platforms, the cDNA microarray developed at the Spanish National Cancer Centre and an oligonucleotide microarray. RESULTS: We identified five clusters of genes, the expression of which varied significantly among the samples. Genes in these clusters seemed to be functionally related to different cellular processes such as proliferation, inflammatory response, and T-cell or B-cell lineages. Regardless of the microarray platform used, overexpression of genes in the proliferation signature was associated significantly with shorter survival of patients. This proliferation signature included genes commonly associated with the cell cycle, such as CCNA, CCNB, TOP2A, and PCNA. Moreover the PTCL proliferation signature showed a statistically significant inverse correlation with clusters of the inflammatory response (P < .0001), as well as with the percentage of CD68(+) cells. CONCLUSION: Our findings indicate that proliferation could be an important factor in evaluating nodal PTCL outcome and may help to define a more aggressive phenotype.

Authors
Cuadros, M; Dave, SS; Jaffe, ES; Honrado, E; Milne, R; Alves, J; Rodríguez, J; Zajac, M; Benitez, J; Staudt, LM; Martinez-Delgado, B
MLA Citation
Cuadros, Marta, et al. “Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas..” J Clin Oncol, vol. 25, no. 22, Aug. 2007, pp. 3321–29. Pubmed, doi:10.1200/JCO.2006.09.4474.
PMID
17577022
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
22
Publish Date
2007
Start Page
3321
End Page
3329
DOI
10.1200/JCO.2006.09.4474

Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.

Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease.

Authors
Annunziata, CM; Davis, RE; Demchenko, Y; Bellamy, W; Gabrea, A; Zhan, F; Lenz, G; Hanamura, I; Wright, G; Xiao, W; Dave, S; Hurt, EM; Tan, B; Zhao, H; Stephens, O; Santra, M; Williams, DR; Dang, L; Barlogie, B; Shaughnessy, JD; Kuehl, WM; Staudt, LM
MLA Citation
Annunziata, Christina M., et al. “Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma..” Cancer Cell, vol. 12, no. 2, Aug. 2007, pp. 115–30. Pubmed, doi:10.1016/j.ccr.2007.07.004.
PMID
17692804
Source
pubmed
Published In
Cancer Cell
Volume
12
Issue
2
Publish Date
2007
Start Page
115
End Page
130
DOI
10.1016/j.ccr.2007.07.004

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.

Authors
Lenz, G; Nagel, I; Siebert, R; Roschke, AV; Sanger, W; Wright, GW; Dave, SS; Tan, B; Zhao, H; Rosenwald, A; Muller-Hermelink, HK; Gascoyne, RD; Campo, E; Jaffe, ES; Smeland, EB; Fisher, RI; Kuehl, WM; Chan, WC; Staudt, LM
MLA Citation
Lenz, Georg, et al. “Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma..” J Exp Med, vol. 204, no. 3, Mar. 2007, pp. 633–43. Pubmed, doi:10.1084/jem.20062041.
PMID
17353367
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
204
Issue
3
Publish Date
2007
Start Page
633
End Page
643
DOI
10.1084/jem.20062041

Drs. Dave and Staudt reply [5]

Authors
Dave, SS; Staudt, LM
MLA Citation
Dave, S. S., and L. M. Staudt. “Drs. Dave and Staudt reply [5].” New England Journal of Medicine, vol. 355, no. 10, Sept. 2006. Scopus, doi:10.1056/NEJMc061833.
Source
scopus
Published In
The New England Journal of Medicine
Volume
355
Issue
10
Publish Date
2006
Start Page
1064
DOI
10.1056/NEJMc061833

Gene expression signatures and outcome prediction in mature B-cell malignancies.

Non-Hodgkin's lymphomas comprise a diverse group of diseases that are subclassified by the state of differentiation of the malignant B cells, presence of specific cytogenetic abnormalities, and characteristic morphology. Gene expression profiling has revealed that within each category of non-Hodgkin's lymphoma, there exists a significant molecular heterogeneity that can be reflected in differences in tumor behavior and patient outcome. Appreciation of gene expression signatures that are associated with patient outcome will allow better prognostication of disease course and aid the application of molecularly selective patients to improve patient outcome.

Authors
Dave, SS
MLA Citation
Dave, Sandeep S. “Gene expression signatures and outcome prediction in mature B-cell malignancies..” Curr Treat Options Oncol, vol. 7, no. 4, July 2006, pp. 261–69.
PMID
16916486
Source
pubmed
Published In
Current Treatment Options in Oncology
Volume
7
Issue
4
Publish Date
2006
Start Page
261
End Page
269

Molecular diagnosis of Burkitt's lymphoma.

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt's lymphoma from diffuse large-B-cell lymphoma. METHODS: Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. RESULTS: A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt's lymphoma. Burkitt's lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-kappaB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt's lymphoma, suggesting they represent cases of Burkitt's lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt's lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. CONCLUSIONS: Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt's lymphoma from diffuse large-B-cell lymphoma.

Authors
Dave, SS; Fu, K; Wright, GW; Lam, LT; Kluin, P; Boerma, E-J; Greiner, TC; Weisenburger, DD; Rosenwald, A; Ott, G; Müller-Hermelink, H-K; Gascoyne, RD; Delabie, J; Rimsza, LM; Braziel, RM; Grogan, TM; Campo, E; Jaffe, ES; Dave, BJ; Sanger, W; Bast, M; Vose, JM; Armitage, JO; Connors, JM; Smeland, EB; Kvaloy, S; Holte, H; Fisher, RI; Miller, TP; Montserrat, E; Wilson, WH; Bahl, M; Zhao, H; Yang, L; Powell, J; Simon, R; Chan, WC; Staudt, LM; Lymphoma/Leukemia Molecular Profiling Project,
MLA Citation
Dave, Sandeep S., et al. “Molecular diagnosis of Burkitt's lymphoma..” N Engl J Med, vol. 354, no. 23, June 2006, pp. 2431–42. Pubmed, doi:10.1056/NEJMoa055759.
PMID
16760443
Source
pubmed
Published In
The New England Journal of Medicine
Volume
354
Issue
23
Publish Date
2006
Start Page
2431
End Page
2442
DOI
10.1056/NEJMoa055759

A loss-of-function RNA interference screen for molecular targets in cancer.

The pursuit of novel therapeutic agents in cancer relies on the identification and validation of molecular targets. Hallmarks of cancer include self-sufficiency in growth signals and evasion from apoptosis; genes that regulate these processes may be optimal for therapeutic attack. Here we describe a loss-of-function screen for genes required for the proliferation and survival of cancer cells using an RNA interference library. We used a doxycycline-inducible retroviral vector for the expression of small hairpin RNAs (shRNAs) to construct a library targeting 2,500 human genes. We used retroviral pools from this library to infect cell lines representing two distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like DLBCL and germinal centre B-cell-like DLBCL. Each vector was engineered to contain a unique 60-base-pair 'bar code', allowing the abundance of an individual shRNA vector within a population of transduced cells to be measured using microarrays of the bar-code sequences. We observed that a subset of shRNA vectors was depleted from the transduced cells after three weeks in culture only if shRNA expression was induced. In activated B-cell-like DLBCL cells, but not germinal centre B-cell-like DLBCL cells, shRNAs targeting the NF-kappaB pathway were depleted, in keeping with the essential role of this pathway in the survival of activated B-cell-like DLBCL. This screen uncovered CARD11 as a key upstream signalling component responsible for the constitutive IkappaB kinase activity in activated B-cell-like DLBCL. The methodology that we describe can be used to establish a functional taxonomy of cancer and help reveal new classes of therapeutic targets distinct from known oncogenes.

Authors
Ngo, VN; Davis, RE; Lamy, L; Yu, X; Zhao, H; Lenz, G; Lam, LT; Dave, S; Yang, L; Powell, J; Staudt, LM
MLA Citation
Ngo, Vu N., et al. “A loss-of-function RNA interference screen for molecular targets in cancer..” Nature, vol. 441, no. 7089, May 2006, pp. 106–10. Pubmed, doi:10.1038/nature04687.
PMID
16572121
Source
pubmed
Published In
Nature
Volume
441
Issue
7089
Publish Date
2006
Start Page
106
End Page
110
DOI
10.1038/nature04687

Gene expression profiling and outcome prediction in non-Hodgkin lymphoma.

Gene expression profiling with microarrays has provided new insights into the molecular biology of tumors can that underlie differences in responses to therapy and patient outcomes. In diffuse large B-cell lymphoma, gene expression profiling has revealed at least 2 diseases that are strikingly different in their response to chemotherapy and the inhibition of critical oncogenic pathways. In follicular lymphoma, gene expression profiling showed that the host immune response to tumors is an important determinant of outcome and can strongly predict survival at the time of diagnosis. The application of immunologic therapies that modify the host immune response could have a major effect on survival in patients with follicular lymphoma. Thus, the application of gene expression profiling in non-Hodgkin lymphoma provides important prognostic information at the time of diagnosis and can be translated into therapeutic options that improve patient outcomes.

Authors
Dave, S
MLA Citation
Dave, Sandeep. “Gene expression profiling and outcome prediction in non-Hodgkin lymphoma..” Biol Blood Marrow Transplant, vol. 12, no. 1 Suppl 1, Jan. 2006, pp. 50–52. Pubmed, doi:10.1016/j.bbmt.2005.10.017.
PMID
16399585
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
12
Issue
1 Suppl 1
Publish Date
2006
Start Page
50
End Page
52
DOI
10.1016/j.bbmt.2005.10.017

Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling.

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.

Authors
Fu, K; Weisenburger, DD; Greiner, TC; Dave, S; Wright, G; Rosenwald, A; Chiorazzi, M; Iqbal, J; Gesk, S; Siebert, R; De Jong, D; Jaffe, ES; Wilson, WH; Delabie, J; Ott, G; Dave, BJ; Sanger, WG; Smith, LM; Rimsza, L; Braziel, RM; Müller-Hermelink, HK; Campo, E; Gascoyne, RD; Staudt, LM; Chan, WC; Lymphoma/Leukemia Molecular Profiling Project,
MLA Citation
Fu, Kai, et al. “Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling..” Blood, vol. 106, no. 13, Dec. 2005, pp. 4315–21. Pubmed, doi:10.1182/blood-2005-04-1753.
PMID
16123218
Source
pubmed
Published In
Blood
Volume
106
Issue
13
Publish Date
2005
Start Page
4315
End Page
4321
DOI
10.1182/blood-2005-04-1753

Immune signatures in follicular lymphoma.

Authors
Hong, W-J; Warnke, R; Chu, G
MLA Citation
Hong, Wan-Jen, et al. “Immune signatures in follicular lymphoma..” N Engl J Med, vol. 352, no. 14, Apr. 2005, pp. 1496–97.
PMID
15818776
Source
pubmed
Published In
The New England Journal of Medicine
Volume
352
Issue
14
Publish Date
2005
Start Page
1496
End Page
1497

Lymphoma-infiltrating immune cells.

Authors
Gajewski, TF
MLA Citation
Gajewski, Thomas F. “Lymphoma-infiltrating immune cells..” N Engl J Med, vol. 352, no. 7, Feb. 2005, pp. 724–25.
PMID
15719444
Source
pubmed
Published In
The New England Journal of Medicine
Volume
352
Issue
7
Publish Date
2005
Start Page
724
End Page
725

The biology of human lymphoid malignancies revealed by gene expression profiling.

Gene expression profiling provides a quantitative molecular framework for the study of human lymphomas. This genomic technology has revealed that existing diagnostic categories are comprised of multiple molecularly and clinically distinct diseases. Diffuse large B-cell lymphoma (DLBCL), for example, consists of three gene expression subgroups, termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). These DLBCL subgroups arise from different stages of normal B-cell differentiation, utilize distinct oncogenic mechanisms, and differ in their ability to be cured by chemotherapy. Key regulatory factors and their target genes are differentially expressed among these subgroups, including BCL-6, Blimp-1, and XBP1. ABC DLBCL and PMBL depend upon constitutive activation of the NF-kappaB pathway for their survival but GCB DLBCL does not, demonstrating that this pathway is a potential therapeutic target for certain DLBCL subgroups. In DLBCL, mantle cell lymphoma, and follicular lymphoma, gene expression profiling has also been used to create gene expression-based models of survival, which have identified the biological characteristics of the tumors that influence their clinical behavior. In mantle cell lymphoma, the length of survival following diagnosis is primarily influenced by the tumor proliferation rate, which can be quantitatively measured by a proliferation gene expression "signature." Based on this accurate measure, the proliferation rate can now be viewed as an integration of several oncogenic lesions that each increase progression from the G1 to the S phase of the cell cycle. In DLBCL and follicular lymphoma, gene expression profiling has revealed that the molecular characteristics of non-malignant tumor-infiltrating immune cells have a major influence on the length of survival. The implications of these insights for the diagnosis and treatment of non-Hodgkin lymphomas are discussed.

Authors
Staudt, LM; Dave, S
MLA Citation
Staudt, Louis M., and Sandeep Dave. “The biology of human lymphoid malignancies revealed by gene expression profiling..” Adv Immunol, vol. 87, 2005, pp. 163–208. Pubmed, doi:10.1016/S0065-2776(05)87005-1.
PMID
16102574
Source
pubmed
Published In
Advances in Immunology
Volume
87
Publish Date
2005
Start Page
163
End Page
208
DOI
10.1016/S0065-2776(05)87005-1

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Authors
Dave, SS; Wright, G; Tan, B; Rosenwald, A; Gascoyne, RD; Chan, WC; Fisher, RI; Braziel, RM; Rimsza, LM; Grogan, TM; Miller, TP; LeBlanc, M; Greiner, TC; Weisenburger, DD; Lynch, JC; Vose, J; Armitage, JO; Smeland, EB; Kvaloy, S; Holte, H; Delabie, J; Connors, JM; Lansdorp, PM; Ouyang, Q; Lister, TA; Davies, AJ; Norton, AJ; Muller-Hermelink, HK; Ott, G; Campo, E; Montserrat, E; Wilson, WH; Jaffe, ES; Simon, R; Yang, L; Powell, J; Zhao, H; Goldschmidt, N; Chiorazzi, M; Staudt, LM
MLA Citation
Dave, Sandeep S., et al. “Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells..” N Engl J Med, vol. 351, no. 21, Nov. 2004, pp. 2159–69. Pubmed, doi:10.1056/NEJMoa041869.
PMID
15548776
Source
pubmed
Published In
The New England Journal of Medicine
Volume
351
Issue
21
Publish Date
2004
Start Page
2159
End Page
2169
DOI
10.1056/NEJMoa041869

BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma.

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup.

Authors
Iqbal, J; Sanger, WG; Horsman, DE; Rosenwald, A; Pickering, DL; Dave, B; Dave, S; Xiao, L; Cao, K; Zhu, Q; Sherman, S; Hans, CP; Weisenburger, DD; Greiner, TC; Gascoyne, RD; Ott, G; Müller-Hermelink, HK; Delabie, J; Braziel, RM; Jaffe, ES; Campo, E; Lynch, JC; Connors, JM; Vose, JM; Armitage, JO; Grogan, TM; Staudt, LM; Chan, WC
MLA Citation
Iqbal, Javeed, et al. “BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma..” Am J Pathol, vol. 165, no. 1, July 2004, pp. 159–66. Pubmed, doi:10.1016/s0002-9440(10)63284-1.
PMID
15215171
Source
pubmed
Published In
The American Journal of Pathology
Volume
165
Issue
1
Publish Date
2004
Start Page
159
End Page
166
DOI
10.1016/s0002-9440(10)63284-1

Cost-effectiveness considerations in the treatment of essential thrombocythemia.

Factors that influence the choice of anagrelide, hydroxyurea, or interferon-alfa (IFN-alpha) for treatment of essential thrombocythemia include efficacy, toxicity, and cost. Anagrelide has the US Food and Drug Administration's approval to be used for treating patients with thrombocythemia secondary to chronic myeloproliferative disorders. In contrast, the use of IFN-alpha and hydroxyurea are considered "off-label." We performed an incremental cost-effectiveness analysis to compare anagrelide, hydroxyurea, and IFN-alpha for treating essential thrombocythemia, in terms of estimated impact on life expectancy. The case used for this analysis was of a 40-year-old man with essential thrombocythemia. Clinical assumptions were based on information obtained from nonrandomized clinical trials, and the economic assumptions were derived from information abstracted from observational studies. Lifelong treatment use of anagrelide versus hydroxyurea would cost approximately $72,000 per additional year of life gained, while the use of IFN-alpha was found to be both more costly and less effective than anagrelide. The results were very sensitive to the risk of leukemia caused by hydroxyurea, with an incremental cost-effectiveness of anagrelide compared with hydroxyurea of $156,969 per additional year of life gained if the lifetime leukemia risk drops from a baseline of .08 to.05. Given that many commonly used medical interventions cost in the range of $50,000 to $100,000 per year of life gained, and the generally poor outcome associated with treatment-related leukemia that can result from hydroxyurea, anagrelide could be considered a therapeutic alternative that is clinically effective at an acceptable cost.

Authors
Golub, R; Adams, J; Dave, S; Bennett, CL
MLA Citation
Golub, Robert, et al. “Cost-effectiveness considerations in the treatment of essential thrombocythemia..” Semin Oncol, vol. 29, no. 3 Suppl 10, June 2002, pp. 28–32.
PMID
12096355
Source
pubmed
Published In
Seminars in Oncology
Volume
29
Issue
3 Suppl 10
Publish Date
2002
Start Page
28
End Page
32

Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase.

Familial amyotrophic lateral sclerosis (FALS) is an autosomal dominant neurodegenerative disorder affecting motor neurons and is associated with mutations in the Cu,Zn superoxide dismutase gene (SOD1) in a subset (approximately 15%) of FALS families. We analyzed 158 FALS patients from 27 families with mutations in SOD1. The mean age of onset was 45.5 +/- 8.9 years, and the mean duration of disease was 3.4 years. Forty-seven different mutations in SOD1 of FALS patients have been described worldwide. In North America, the ala4val mutation is the most common. In our patients, the ala4val mutation was associated with the most rapid progression of disease. The mean duration of disease was 1.0 +/- 0.4 years, which is significantly less than the mean duration of disease for FALS patients with mutations in SOD1 other than ala4val (p < 0.001). The duration of disease for the glu100gly mutation, 5.1 +/- 3.3 years, was significantly longer than the ala4val mutation (p < 0.001). We constructed Kaplan-Meier survival curves for the age of onset and duration of the disease for three groups of patients having mutations in SOD1: (1) ala4val; (2) glu100gly; and (3) ala4val, gly37arg, his43arg, gly85arg, gly93ala, glu100gly, leu106val, ile113thr, leu144phe, and val148gly, i.e., the entire patient population. There was no correlation between the genotype and the age of onset; 50% of affected individuals developed symptoms of ALS by the age of 47 years. As more data are collected, a more accurate prognostication of a patient's survival may be possible for specific SOD1 mutations.

Authors
Juneja, T; Pericak-Vance, MA; Laing, NG; Dave, S; Siddique, T
MLA Citation
Juneja, T., et al. “Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase..” Neurology, vol. 48, no. 1, Jan. 1997, pp. 55–57. Pubmed, doi:10.1212/wnl.48.1.55.
PMID
9008494
Source
pubmed
Published In
Neurology
Volume
48
Issue
1
Publish Date
1997
Start Page
55
End Page
57
DOI
10.1212/wnl.48.1.55

ATP receptor activation potentiates a voltage-dependent Ca channel in hippocampal neurons.

Activation of a purinergic P2 receptor by adenosine 5'-triphosphate (ATP) has previously been shown to open a non-selective cation channel with a reversal potential of approximately 0 mV. We examined the effect of P2 receptor activation on voltage-gated ionic currents in acutely isolated CA3 pyramidal neurons from guinea pig hippocampus using the whole-cell-patch technique. Under conditions designed to isolate current through voltage-dependent Ca channels (ICa), ATP (50 microM) potentiated ICa by 36%. This increase in ICa desensitized back to control levels within 4 min. In contrast to the non-selective cation channel, ICa elicited from a holding potential (HP) of -100 mV showed significant potentiation in response to ATP when depolarized to a test potential (TP) of -10 mV but showed no effect on ICa when the same neuron was alternately depolarized to TP = -70 mV. No change in holding current at HP = -100 mV occurred. Tail currents were unaffected by ATP exposure suggesting that ICa potentiation was not due to modulation of L-type Ca channels. This potentiation was also observed either with ATP-gamma-s, the slowly hydrolyzable ATP analog, or with ATP in the presence of alpha, beta-methylene-ADP, an ectonucleotidase inhibitor, indicating that the effects observed were not due to activation of an adenosine receptor that required ATP hydrolysis. The potentiation of ICa was not observed with the P2X agonist, beta, gamma-methylene-ATP. These results suggest that ATP receptors can modulate voltage- as well as ligand-gated channels permeable to calcium and may play an important role in the dynamics of intracellular Ca2+ in these neurons.

Authors
Dave, S; Mogul, DJ
MLA Citation
Dave, S., and D. J. Mogul. “ATP receptor activation potentiates a voltage-dependent Ca channel in hippocampal neurons..” Brain Res, vol. 715, no. 1–2, Apr. 1996, pp. 208–16. Pubmed, doi:10.1016/0006-8993(95)01588-4.
PMID
8739640
Source
pubmed
Published In
Brain Research
Volume
715
Issue
1-2
Publish Date
1996
Start Page
208
End Page
216
DOI
10.1016/0006-8993(95)01588-4
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