Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma.

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2017-03

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Abstract

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.

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10.1038/leu.2016.243

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Xia, Y, ZY Xu-Monette, A Tzankov, X Li, GC Manyam, V Murty, G Bhagat, S Zhang, et al. (2017). Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma. Leukemia, 31(3). pp. 625–636. 10.1038/leu.2016.243 Retrieved from https://hdl.handle.net/10161/19331.

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Xu-Monette

Zijun Yidan Xu-Monette

Assistant Professor in Pathology

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.

Young

Ken H Young

Professor of Pathology

I am a clinically-oriented diagnostic physician with clinical expertise in the pathologic diagnosis of hematologic cancers including tumors of the bone marrow, lymphoid tissue, spleen and pre-malignant hematologic conditions. Another area of interest is blood cancer classification with molecular and genetic profiling. In my research program, we focus on molecular mechanisms of tumor progression, cell-of-origin, biomarkers, and novel therapeutic strategies in lymphoma, myeloma and leukemia. In addition to patient care and translational research, medical education and scientific communication are also part of interest. I provide persistent support for the physician-scientist program and Blood Cancer Pathology program in the department and cancer center. Many residents, fellows, graduates and postdocs have worked and been trained in our program. We perform comprehensive clinical and research functions that include bone marrow, lymphoma pathology, clinical flow cytometry, cytogenetics, molecular diagnostics and outside services.

I am currently the director of hematopathology division that provides diagnostic consultation services and relevant specialized testing for patients with various types of acute and chronic leukemia, lymphoma and benign hematologic disorders. I am specialized in the diagnosis of hematological disorders, including acute and chronic leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, B and T-cell lymphomas, Hodgkin lymphoma, cutaneous and orbital lymphomas and benign bone marrow and lymph node disorders. 

Our group has been supported by various funding resources since 2006 and has published 318 original peer-reviewed articles and 56 review articles, many in high- impact journals (Nature Clin Onc Rev, JCO, JAMA, Lancet, Blood, JHO, Leukemia and Clinical Cancer Research). The contributions to the hematology field include the development of novel diagnostic algorithms, molecular and genetic biomarkers for classification of blood cancer, lymphoid neoplasms and lymphoid diseases.




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