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:

Prognostic factors, therapeutic approaches, and distinct immunobiologic features in patients with primary mediastinal large B-cell lymphoma on long-term follow-up.

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL) without prognostic factors or a single standard of treatment clearly defined. In this study we performed retrospective analysis for clinical outcomes of 166 patients with PMBCL. In overall PMBCL, higher International Prognostic Index, stage, Ki-67 proliferation index, and positron emission tomography (PET) maximum standardized uptake values (SUVmax) at diagnosis were significantly associated with poorer survival, whereas MUM1 expression and higher peripheral blood lymphocyte/monocyte ratios were significantly associated with better survival. Patients who received R-HCVAD or R-EPOCH had better clinical outcome than did those who received the standard treatment R-CHOP. Treatment response and end-of-treatment PET SUVmax had remarkable correlations with survival outcome. In patients with refractory or relapsed PMBCL, stem cell transplant significantly improved overall survival. PMBCL had distinct gene expression signatures compared with overall DLBCL-NOS but not with DLBCL with PD-L1/PD-L2 amplification. PMBCL also showed higher PD-L2 expression in B-cells, lower PD-1 expression in T-cells, and higher CTLA-4 expression in T-cells and distinct miRNA signatures compared with DLBCL-NOS. The prognostic factors, effectiveness of treatment, transcriptional and epigenetic signatures, and immunologic features revealed by this study enrich our understanding of PMBCL biology and support future treatment strategy.
Authors
Zhou, H; Xu-Monette, ZY; Xiao, L; Strati, P; Hagemeister, FB; He, Y; Chen, H; Li, Y; Manyam, GC; Li, Y; Montes-Moreno, S; Piris, MA; Young, KH
MLA Citation
Zhou, Hui, et al. “Prognostic factors, therapeutic approaches, and distinct immunobiologic features in patients with primary mediastinal large B-cell lymphoma on long-term follow-up.Blood Cancer J, vol. 10, no. 5, May 2020, p. 49. Pubmed, doi:10.1038/s41408-020-0312-7.
URI
https://scholars.duke.edu/individual/pub1439892
PMID
32366834
Source
pubmed
Published In
Blood Cancer Journal
Volume
10
Published Date
Start Page
49
DOI
10.1038/s41408-020-0312-7

Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation.

BACKGROUND: Aberrant activation of DNA damage response (DDR) is a major cause of chemoresistance in colorectal cancer (CRC). CHK1 is upregulated in CRC and contributes to therapeutic resistance. We investigated the upstream signaling pathways governing CHK1 activation in CRC. METHODS: We identified CHK1-binding proteins by mass spectrometry analysis. We analyzed the biologic consequences of knockout or overexpression of TRAF4 using immunoblotting, immunoprecipitation, and immunofluorescence. CHK1 and TRAF4 ubiquitination was studied in vitro and in vivo. We tested the functions of TRAF4 in CHK1 phosphorylation and CRC chemoresistance by measuring cell viability and proliferation, anchorage-dependent and -independent cell growth, and mouse xenograft tumorigenesis. We analyzed human CRC specimens by immunohistochemistry. RESULTS: TRAF4 catalyzed the ubiquitination of CHK1 in multiple CRC cell lines. Following DNA damage, ubiquitination of CHK1 at K132 by TRAF4 is required for CHK1 phosphorylation and activation mediated by ATR. Notably, TRAF4 was highly expressed in chemotherapy-resistant CRC specimens and positively correlated with phosphorylated CHK1. Furthermore, depletion of TRAF4 impaired CHK1 activity and sensitized CRC cells to fluorouracil and other chemotherapeutic agents in vitro and in vivo. CONCLUSIONS: These data reveal two novel steps required for CHK1 activation in which TRAF4 serves as a critical intermediary and suggest that inhibition of the ATR-TRAF4-CHK1 signaling may overcome CRC chemoresistance.
Authors
Yu, X; Li, W; Liu, H; Deng, Q; Wang, X; Hu, H; Xu-Monette, ZY; Xiong, W; Lu, Z; Young, KH; Wang, W; Li, Y
MLA Citation
Yu, Xinfang, et al. “Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation.J Hematol Oncol, vol. 13, no. 1, May 2020, p. 40. Pubmed, doi:10.1186/s13045-020-00869-3.
URI
https://scholars.duke.edu/individual/pub1440834
PMID
32357935
Source
pubmed
Published In
Journal of Hematology & Oncology
Volume
13
Published Date
Start Page
40
DOI
10.1186/s13045-020-00869-3

LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma.

Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.
Authors
Keane, C; Law, SC; Gould, C; Birch, S; Sabdia, MB; Merida de Long, L; Thillaiyampalam, G; Abro, E; Tobin, JW; Tan, X; Xu-Monette, ZY; Young, KH; Gifford, G; Gabreilli, S; Stevenson, WS; Gill, A; Talaulikar, D; Jain, S; Hernandez, A; Halliday, S-J; Bird, R; Cross, D; Hertzberg, M; Gandhi, MK
MLA Citation
Keane, Colm, et al. “LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma.Blood Adv, vol. 4, no. 7, Apr. 2020, pp. 1367–77. Pubmed, doi:10.1182/bloodadvances.2019001390.
URI
https://scholars.duke.edu/individual/pub1436646
PMID
32267932
Source
pubmed
Published In
Blood Adv
Volume
4
Published Date
Start Page
1367
End Page
1377
DOI
10.1182/bloodadvances.2019001390

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma. METHODS: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens' immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry. RESULTS: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHMhigh) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell-like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHMhigh groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8+ T cells was significantly lower in IGHV SHMhigh than in SHMlow patients with activated B-cell-like DLBCL, whereas PD-1 expression in CD4+ T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHMhigh than in SHMlow patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM. CONCLUSIONS: These results show for the first time that IGV SHMhigh and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies.
Authors
Xu-Monette, ZY; Li, J; Xia, Y; Crossley, B; Bremel, RD; Miao, Y; Xiao, M; Snyder, T; Manyam, GC; Tan, X; Zhang, H; Visco, C; Tzankov, A; Dybkaer, K; Bhagat, G; Tam, W; You, H; Hsi, ED; van Krieken, JH; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Piris, MA; Winter, JN; Medeiros, JT; Xu, B; Li, Y; Kirsch, I; Young, KH
MLA Citation
Xu-Monette, Zijun Y., et al. “Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.J Immunother Cancer, vol. 7, no. 1, Oct. 2019, p. 272. Pubmed, doi:10.1186/s40425-019-0730-x.
URI
https://scholars.duke.edu/individual/pub1416613
PMID
31640780
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date
Start Page
272
DOI
10.1186/s40425-019-0730-x

Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations.

BACKGROUND:The clinical presentation of patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphoma (DLBCL) is different from their HCV-negative counterparts, but the underlying molecular and pathological characteristics are largely under investigated. The virus has a role in lymphomagenesis, as witnessed by the curative potential of antiviral therapy in HCV-related low-grade B-cell lymphomas. METHODS:We performed a case-control study including 44 HCV-positive cases of de novo DLBCL, comparing them with 132 HCV-negative patients as controls (ratio 3 to 1). Cases and controls were matched for age, lactate dehydrogenase level and international prognostic index at presentation. Patients were studied by gene expression profiling for cell-of-origin determination and to perform differential expression analysis between groups, fluorescence in-situ hybridisation and immunohistochemistry for MYC, BCL2 and BCL6, TP53 mutations, and diagnostic specimens reviewed to exclude transformation from low-grade lymphoma. RESULTS:Compared to the HCV-negative controls, patients with HCV-positive de novo DLBCL had differential expression of genes that regulate innate immune response and modulate apoptotic pathways, have higher proliferative index, and lack BCL2 translocations. CONCLUSIONS:HCV-positive DLBCL have distinct molecular and pathological features compared to the HCV-negative counterparts.
Authors
Visco, C; Wang, J; Tisi, MC; Deng, L; D'Amore, ESG; Tzankov, A; Montes-Moreno, S; Dybkær, K; Bhagat, G; Hsi, ED; van Krieken, JH; Ponzoni, M; Ferreri, AJM; Møller, MB; Piris, MA; Medeiros, LJ; Xu-Monette, ZY; Young, KH
MLA Citation
Visco, Carlo, et al. “Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations.British Journal of Cancer, vol. 117, no. 11, Nov. 2017, pp. 1685–88. Epmc, doi:10.1038/bjc.2017.345.
URI
https://scholars.duke.edu/individual/pub1405000
PMID
28949959
Source
epmc
Published In
British Journal of Cancer
Volume
117
Published Date
Start Page
1685
End Page
1688
DOI
10.1038/bjc.2017.345