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:

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

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

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

Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88L265P mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88L265P and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4NS/MS), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4NS/MS including those with TP53 mutations. In conclusion, genetic testing for MYD88L265P, TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.
Authors
Wang, Y; Gali, VL; Xu-Monette, ZY; Sano, D; Thomas, SK; Weber, DM; Zhu, F; Fang, X; Deng, M; Zhang, M; Hagemeister, FB; Li, Y; Orlowski, RZ; Lee, HC; Young, KH
MLA Citation
Wang, Yingjun, et al. “Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia.Neoplasia, vol. 23, no. 4, Apr. 2021, pp. 361–74. Pubmed, doi:10.1016/j.neo.2021.02.002.
URI
https://scholars.duke.edu/individual/pub1476516
PMID
33735664
Source
pubmed
Published In
Neoplasia
Volume
23
Published Date
Start Page
361
End Page
374
DOI
10.1016/j.neo.2021.02.002

Cell of Origin Classification of DLBCL Using Targeted NGS Expression Profiling and Deep Learning

<jats:p>Introduction: Targeted RNA sequencing using Next Generation Sequencing (NGS) has significant advantages over transcriptome sequencing. In addition to information on mutations, fusion and alternative splicing, RNA quantification using targeted RNA sequencing is sensitive, reproducible and provides better dynamic range. We used targeted RNA sequencing for RNA profiling of diffuse large B-cell lymphoma (DLBCL) and explored its utility in the sub-classification of DLBC to ABC and GCB. Method: RNA extracted from 441 FFPE lymphnode samples with DLBC lymphoma and sequenced targeting 1408 genes. These cases were previously subclassified as ABC vs GCB using expression profiling and immunohistochemistry. We first normalized RNA expression data to PAX5 expression, then we tried to narrow down important markers using univariate significance tests. Setting the cutoff for false discovery rate at 0.0001, 48 variables remained significant, including 46 RNA levels and two genes (MYD88 and EZH2) mutation status. Using 60% of samples as training set, we used multiple statistical approaches for classification. Deep learning emerged as the best approach. We used autoencoder with 5 hidden layers and developed a model for classification of ABC vs GCB. To further improve on classification, we divided patients in each subgroup based on survival using simple tree model. In this tree model, expression level of CD58 emerged as a powerful prognostic marker for the ABC group and RLTPR expression in the GCB group. Results: Using probability of scoring developed based on deep learning and logestic regression, approximately 30% of the cases had a score between 0.5 and 0.75. For the remaining 70% of patients, the ABC vs GCB classification showed sensitivity and specificity of 96% and 97% for the testing set. We also applied the same approach to 60 independent cases classified using NanoString (Lymph2Cx). Our model showed sensitivity and specificity of 96% and 97% in the NanoString independent cases. Using the tree model for further classification of the ABC and GCB classes, CD58 mRNA levels separated the ABC group into two subgroups (ABC1 and ABC2) and RLTPR mRNA separated the GCB into two subgroups (GCB1 and GCB2) with significant difference in overall survival (P=0.0010) and progression-free survival (PFS) (P=0.0027). Conclusion: Targeted RNA sequencing is very reliable and practical for the subclassification of DLBCL and can provide clinical-grade reproducible test for prognostically subclassification of DLBCL.</jats:p> <jats:p>Figure</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Albitar: Genomic Testing Ccoperative: Employment, Equity Ownership. De Dios:Genomic Testing Ccoperative: Employment. Tam:Takeda: Consultancy; Paragon Genomics: Consultancy. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&amp;Abbvie Biotherapeutics Inc: Patents &amp; Royalties: US8,603,477 B2; Jazz: Consultancy. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Kantarjian:Ariad: Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; BMS: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding.</jats:p> </jats:sec>
Authors
Albitar, M; Xu-Monette, ZY; Shahbaba, B; De Dios, I; Wang, Y; Manman, D; Tzankov, A; Visco, C; Bhagat, G; Dybkær, K; Tam, W; Hsi, ED; Ponzoni, M; Ferreri, AJM; Moller, M; Piris, MA; Van Krieken, JHJM; Zu, Y; Ma, W; Kantarjian, HM; Li, Y; Young, KH
MLA Citation
Albitar, Maher, et al. “Cell of Origin Classification of DLBCL Using Targeted NGS Expression Profiling and Deep Learning.” Blood, vol. 134, no. Supplement_1, American Society of Hematology, 2019, pp. 2891–2891. Crossref, doi:10.1182/blood-2019-126927.
URI
https://scholars.duke.edu/individual/pub1470247
Source
crossref
Published In
Blood
Volume
134
Published Date
Start Page
2891
End Page
2891
DOI
10.1182/blood-2019-126927