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 percent 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: DNA 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA092625-06
Application #
7136452
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wu, Roy S
Project Start
2001-08-02
Project End
2011-06-30
Budget Start
2006-08-16
Budget End
2007-06-30
Support Year
6
Fiscal Year
2006
Total Cost
$3,219,425
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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