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:

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. 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

Clinical Significance of PD-1 and PD-L1 Expression and Ongoing Interaction in the Tumor Microenvironment in Diffuse Large B Cell Lymphoma (DLBCL) Treated with R-CHOP

Authors
Xu-Monette, ZY; Yu, L; Thai, T; Adams, L; Roscoe, N; Manyam, G; Visco, C; Tzankov, A; Dybkaer, K; Bhagat, G; Chiu, A; Tam, W; Zu, Y; Hsi, ED; Van Krieken, JHJM; Huh, J; Ponzoni, M; Ferreri, A; Moller, MB; Piris, MA; Winter, JN; Medeiros, LJ; Rassidakis, G; Vaupel, CA; Li, Y; Dakappagari, N; Young, KH
URI
https://scholars.duke.edu/individual/pub1405119
Source
wos
Published In
Blood
Volume
130
Published Date

Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma.

PURPOSE: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. EXPERIMENTAL DESIGN: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients. RESULTS: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts. CONCLUSIONS: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. ©2016 AACR.
Authors
Xu-Monette, ZY; Deng, Q; Manyam, GC; Tzankov, A; Li, L; Xia, Y; Wang, X-X; Zou, D; Visco, C; Dybkær, K; Li, J; Zhang, L; Liang, H; Montes-Moreno, S; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; van Krieken, JH; Huh, J; Ponzoni, M; Ferreri, AJM; Parsons, BM; Møller, MB; Wang, SA; Miranda, RN; Piris, MA; Winter, JN; Medeiros, LJ; Li, Y; Young, KH
MLA Citation
Xu-Monette, Zijun Y., et al. “Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma..” Clin Cancer Res, vol. 22, no. 14, July 2016, pp. 3593–605. Pubmed, doi:10.1158/1078-0432.CCR-15-2296.
URI
https://scholars.duke.edu/individual/pub1405012
PMID
26927665
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
22
Published Date
Start Page
3593
End Page
3605
DOI
10.1158/1078-0432.CCR-15-2296

Waldenström macroglobulinemia with extramedullary involvement at initial diagnosis portends a poorer prognosis.

BACKGROUND: The prognostic importance of extramedullary involvement in patients with Waldenström macroglobulinemia (WM) at diagnosis and treatment options for these patients has not been well evaluated. In this study, we investigated the clinical manifestations, biological features, and effect of first-line therapy on the outcome of WM patients diagnosed with extramedullary involvement (EMWM) vs those with only bone marrow involvement (BMWM). METHODS: We analyzed the clinical data of 312 WM patients diagnosed with EMWM (n = 106) and BMWM (n = 206) at The University of Texas MD Anderson Cancer Center from 1994 to 2014. EMWM was confirmed by biopsy, positron emission tomography-computed tomography, or magnetic resonance imaging, and clinical laboratory analyses. RESULTS: Characteristics associated with EMWM were male sex (P = 0.027), age younger than 65 years (P = 0.048), presence of B symptoms (P < 0.001), high serum beta-2 macroglobulin (P < 0.001) level, low serum albumin level (P = 0.036), and cytogenetic abnormalities (P = 0.010). Kaplan-Meier survival analysis results showed that EMWM patients had a significantly shorter median overall survival (P < 0.001) and progression-free survival (PFS) (P < 0.001) than did BMWM patients. Chemotherapy combined with targeted therapy improved PFS for BMWM patients (P = 0.004) but not for EMWM patients. Additionally, initial treatment with rituximab significantly improved the PFS of BMWM patients (P = 0.012) but had no effect on EMWM patients. However, EMWM patients treated with nucleoside analogs attained a better PFS than those who did not (P = 0.021). CONCLUSIONS: We show that extramedullary involvement at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy with nucleoside analogs improved PFS for patients with EMWM. The study provides unique clinical and treatment observations in subtypes of WM patients.
Authors
Cao, X; Ye, Q; Orlowski, RZ; Wang, X; Loghavi, S; Tu, M; Thomas, SK; Shan, J; Li, S; Qazilbash, M; Yin, CC; Weber, D; Miranda, RN; Xu-Monette, ZY; Medeiros, LJ; Young, KH
MLA Citation
Cao, Xin, et al. “Waldenström macroglobulinemia with extramedullary involvement at initial diagnosis portends a poorer prognosis..” J Hematol Oncol, vol. 8, June 2015. Pubmed, doi:10.1186/s13045-015-0172-y.
URI
https://scholars.duke.edu/individual/pub1405027
PMID
26104577
Source
pubmed
Published In
Journal of Hematology & Oncology
Volume
8
Published Date
Start Page
74
DOI
10.1186/s13045-015-0172-y

NF-kappa B Subunit c-Rel Cooperates with Myc and Mutated p53 to Confer Significantly Worse Survival in Patients with Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program

Authors
Li, L; Xu-Monette, ZY; Ok, CY; Tzanko, A; Visco, C; Gisin, N; Montes-Moreno, S; Dybkaer, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; Van Krieken, JHJM; Huh, J; Ponzoni, M; Ferreri, AJM; Moller, MB; Go, RS; Winter, JN; Piris, MA; Medeiros, LJ; Young, KH
URI
https://scholars.duke.edu/individual/pub1405129
Source
wos
Published In
Blood
Volume
124
Published Date