Germinal center (GC) B-cell lymphomas are clinically and genetically heterogeneous disorders. The incidence of the most common GC B-cell lymphomas has increased dramatically in recent years, with a 50% rise in the last generation. The participants of this PO1 believe that additional major breakthroughs in these increasingly common diseases will require a more complete understanding of critical underlying pathogenetic events. For this reason, we propose to address the following hypotheses in this competitive renewal application: 1) defects in DMA damage repair and deregulated immunoglobulin gene rearrangement predispose to oncogenic translocations and the development of lymphomas (F. Alt, Project 1);2) tonic signaling via the B-cell receptor (BCR) pathway and constitutive activation of the canonical and alternative NFicB pathways increases the survival of GC B-cell lymphomas (K. Rajewsky, Project 2);3) deregulated expression of the essential GC transcription factor, BCL6, promotes the development of certain large B-cell lymphomas (R. Dalla-Favera, Project 3);4) specific subtypes of large B-cell lymphoma have unique pathogenetic mechanisms and, likely, rational therapeutic targets (M. Shipp, Project 4);and 5) components of deregulated apoptotic and transcriptional programs in GC B-cell lymphomas can be targeted using a novel chemical strategy termed hydrocarbon stapling (L. Walensky, Project 5). The proposed projects rely heavily on input of and collaboration with investigators in the following Cores: DMA Microarray/Bioinformatics (T. Golub, Core A), Hematopathology (J. Aster, Core B), Biostatistics/Clinical Trials (D. Neuberg/A. Freedman, Core C) and Administration (M. Shipp/K. Rajewsky, Core D). In this PO1, we will utilize carefully designed murine models of GC B-cell lymphomas and highly informative primary human tumors and cell lines to define the most important molecular events in these diseases. Our long-term goal is to identify predisposing factors and molecular bases for the development of GC B-cell lymphomas, improve the diagnosis of specific entities, refine our prognostic assessments and credential rational targets for more effective and specific therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Subcommittee G - Education (NCI)
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Merritt, William D
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Dana-Farber Cancer Institute
United States
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Chapuy, Bjoern; Cheng, Hongwei; Watahiki, Akira et al. (2016) Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease. Blood 127:2203-13
Zhang, Baochun; Calado, Dinis Pedro; Wang, Zhe et al. (2015) An oncogenic role for alternative NF-?B signaling in DLBCL revealed upon deregulated BCL6 expression. Cell Rep 11:715-26
Carey, Christopher D; Gusenleitner, Daniel; Chapuy, Bjoern et al. (2015) Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens. J Mol Diagn 17:19-30
Gostissa, Monica; Bianco, Julia M; Malkin, Daniel J et al. (2013) Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas. Proc Natl Acad Sci U S A 110:2934-9
Yan, Qingsheng; Xu, Rong; Zhu, Liya et al. (2013) BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Mol Cell Biol 33:845-57
Ying, Carol Y; Dominguez-Sola, David; Fabi, Melissa et al. (2013) MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol 14:1084-92
Chen, Linfeng; Monti, Stefano; Juszczynski, Przemyslaw et al. (2013) SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas. Cancer Cell 23:826-38
Rossi, Davide; Rasi, Silvia; Spina, Valeria et al. (2013) Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 121:1403-12
LaBelle, James L; Katz, Samuel G; Bird, Gregory H et al. (2012) A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest 122:2018-31
Kluk, Michael J; Chapuy, Bjoern; Sinha, Papiya et al. (2012) Immunohistochemical detection of MYC-driven diffuse large B-cell lymphomas. PLoS One 7:e33813

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