Zijun Xu-Monette

Overview:

My research efforts have been focused on identifying prognostic and therapeutic biomarkers in B-cell lymphoma. My research interests also include investigation of molecular and immune mechanisms underlying the poor clinical outcomes of lymphoma, the pathogenesis and evolution of drug resistant clones, and development of novel therapies for aggressive B-cell lymphoma.

Positions:

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2009

Michigan Technological University

Grants:

Publications:

EBV-positive high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study.

AIMS: It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL). METHODS AND RESULTS: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL. CONCLUSIONS: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.
Authors
Liu, H; Xu-Monette, ZY; Tang, G; Wang, W; Kim, Y; Yuan, J; Li, Y; Chen, W; Li, Y; Fedoriw, GY; Zhu, F; Fang, X; Luedke, C; Medeiros, LJ; Young, KH; Hu, S
MLA Citation
Liu, Hui, et al. “EBV-positive high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study.Histopathology, Oct. 2021. Pubmed, doi:10.1111/his.14585.
URI
https://scholars.duke.edu/individual/pub1498836
PMID
34637146
Source
pubmed
Published In
Histopathology
Published Date
DOI
10.1111/his.14585

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.
Authors
You, H; Xu-Monette, ZY; Wei, L; Nunns, H; Nagy, ML; Bhagat, G; Fang, X; Zhu, F; Visco, C; Tzankov, A; Dybkaer, K; Chiu, A; Tam, W; Zu, Y; Hsi, ED; Hagemeister, FB; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Parsons, BM; Van Krieken, JH; Piris, MA; Winter, JN; Li, Y; Au, Q; Xu, B; Albitar, M; Young, KH
MLA Citation
You, Hua, et al. “Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma.Oncoimmunology, vol. 10, no. 1, 2021, p. 1928365. Pubmed, doi:10.1080/2162402X.2021.1928365.
URI
https://scholars.duke.edu/individual/pub1490053
PMID
34350060
Source
pubmed
Published In
Oncoimmunology
Volume
10
Published Date
Start Page
1928365
DOI
10.1080/2162402X.2021.1928365

MYC protein expression does not correlate with MYC abnormalities detected by FISH but predicts an unfavorable prognosis in de novo acute myeloid leukemia.

While dysregulation of MYC has been implicated in acute myeloid leukemia (AML), the impact of MYC protein expression in AML is less well understood. We investigated the correlation of MYC protein expression by immunohistochemistry (MYC-IHC) with MYC abnormalities and prognosis in adult de novo AML. MYC-IHC in bone marrow of patients with untreated AML (n = 58) was assessed and scored as MYClow (0-40 % of blasts) or MYChigh (> 40 % of blasts). This was correlated with MYC abnormalities by fluorescence in situ hybridization (FISH) and prognosis in the context of cytogenetic risk stratification. Residual myeloid disease at the end of induction was assessed by flow cytometry. MYClow and MYChigh were detected in 24 (41 %) and 34 cases (59 %), respectively. Extra copies of MYC were present in 12 % of cases and were not correlated with level of MYC-IHC. No cases had MYC translocation or amplification. Compared to MYClow patients, MYChigh patients had a shorter overall survival in all cytogenetic risk groups (68 vs. 21 months, p = 0.006) and in the intermediate risk group (61 vs. 21 months, p = 0.046). MYChigh patients had a tendency towards detected residual disease at the end of induction in all cytogenetic risk and intermediate risk groups. Regardless of the underlying mechanisms of MYC dysregulation, high level of MYC protein is expressed in the majority of AML and correlated to worse prognosis. Further studies on MYC dysregulation in leukemogenesis and therapy targeting MYC aberration are warranted.
Authors
Chen, P; Redd, L; Schmidt, Y; Koduru, P; Fuda, F; Montgomery-Goecker, C; Kumar, K; Xu-Monette, Z; Young, K; Collins, R; Chen, W
MLA Citation
Chen, Pu, et al. “MYC protein expression does not correlate with MYC abnormalities detected by FISH but predicts an unfavorable prognosis in de novo acute myeloid leukemia.Leuk Res, vol. 106, July 2021, p. 106584. Pubmed, doi:10.1016/j.leukres.2021.106584.
URI
https://scholars.duke.edu/individual/pub1482372
PMID
33933715
Source
pubmed
Published In
Leuk Res
Volume
106
Published Date
Start Page
106584
DOI
10.1016/j.leukres.2021.106584

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1high) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R+) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1high observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R+ DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
Authors
Deng, M; Zhang, M; Xu-Monette, ZY; Pham, LV; Tzankov, A; Visco, C; Fang, X; Bhagat, G; Zhu, F; Dybkaer, K; Chiu, A; Tam, W; Zu, Y; Hsi, ED; Choi, WWL; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Parsons, BM; van Krieken, JH; Piris, MA; Winter, JN; Hagemeister, F; Alinari, L; Li, Y; Andreeff, M; Xu, B; Young, KH
MLA Citation
Deng, Manman, et al. “XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.J Hematol Oncol, vol. 13, no. 1, Nov. 2020, p. 148. Pubmed, doi:10.1186/s13045-020-00982-3.
URI
https://scholars.duke.edu/individual/pub1464082
PMID
33148342
Source
pubmed
Published In
Journal of Hematology & Oncology
Volume
13
Published Date
Start Page
148
DOI
10.1186/s13045-020-00982-3

A Novel Predictive Model for Idiopathic Multicentric Castleman Disease: The International Castleman Disease Consortium Study.

BACKGROUND: Patients with multicentric Castleman disease (MCD) who are negative for human immunodeficiency virus and human herpesvirus 8 are considered to have idiopathic MCD (iMCD). The clinical presentation of iMCD varies from mild constitutional symptoms to life-threatening symptoms or death. The treatment strategy varies from "watchful waiting" to high-dose chemotherapy. This diverse clinical presentation calls for a classification stratification system that takes into account the severity of the disease. SUBJECTS, MATERIALS, AND METHODS: We analyzed the clinical, laboratory, and pathologic abnormalities and treatment outcomes of 176 patients with iMCD (median follow-up duration 12 years) from the U.S. and China to better understand the characteristics and prognostic factors of this disease. This discovery set of iMCD results was confirmed from the validation set composed of additional 197 patients with iMCD organized from The International Castleman Disease Consortium. RESULTS: Using these data, we proposed and validated the iMCD international prognostic index (iMCD-IPI), which includes parameters related to patient characteristics (age > 40 years), histopathologic features (plasma cell variant), and inflammatory consequences of iMCD (hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion). These five factors stratified patients according to their performance status and extent of organ dysfunction into three broad categories: low risk, intermediate risk, and high risk. The iMCD-IPI score accurately predicted outcomes in the discovery study cohort, and the results were confirmed on the validation study cohort. CONCLUSION: This study represents the largest series of studies on patients with iMCD in the field and proposed a novel risk-stratification model for iMCD-IPI that could be used to guide risk-stratified treatment strategies in patients with iMCD. IMPLICATIONS FOR PRACTICE: Patients with idiopathic multicentric Castleman disease (iMCD) can benefit from care based on clinical symptoms and disease severity. This study in 176 patients with iMCD constructed an iMCD-IPI score based on five clinical factors, including age >40 years, plasmacytic variant subtype, hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion, and stratified patients into three risk categories: low risk, intermediate risk, and high risk. The predictive value was validated in an independent set of 197 patients with iMCD from The International Castleman Disease Consortium. The proposed novel model is valuable for predicting clinical outcome and selecting optimal therapies using clinical parameters.
Authors
Yu, L; Shi, M; Cai, Q; Strati, P; Hagemeister, F; Zhai, Q; Li, L; Fang, X; Li, J; Sun, R; Zhang, S; Yang, H; Wang, Z; Qian, W; Iwaki, N; Sato, Y; Zhang, L; Li, J; Oksenhendler, E; Xu-Monette, ZY; Young, KH
MLA Citation
Yu, Li, et al. “A Novel Predictive Model for Idiopathic Multicentric Castleman Disease: The International Castleman Disease Consortium Study.Oncologist, vol. 25, no. 11, Nov. 2020, pp. 963–73. Pubmed, doi:10.1634/theoncologist.2019-0986.
URI
https://scholars.duke.edu/individual/pub1457153
PMID
32852137
Source
pubmed
Published In
Oncologist
Volume
25
Published Date
Start Page
963
End Page
973
DOI
10.1634/theoncologist.2019-0986