This research program is aimed at identifying new pathogenetic mechanisms in Diffuse Large B-Cell Lymphoma (DLBCL), the most common human lymphoma, as a mean to discover new targets for therapeutic intervention. DLBCL is a heterogeneous malignancy comprising genetically and clinically distinct phenotypes, which are derived from the malignant transformation of germinal center (GC) B cells at different stages of differentiation. Recent analysis of the DLBCL genome has identified a multitude of altered genes, most of which with unknown roles in normal GC physiology and lymphomagenesis. Thus, our program will address these issues by two main complementary approaches. First, we will use novel technologies allowing the analysis of signaling pathways and gene expression on a single cell basis from purified GC B cell subpopulations, as a mean to comprehensively identify the programs that are involved in GC development and potentially altered in DLBCL. Second, we will investigate the function and regulation of two GC ?master regulators?, the activity of which is deregulated in DLBCL via mutational mechanisms as well as via alterations in ?upstream? signaling pathways. The overall program is based on our long-standing experience in studying the biology of the GC reaction in relationship to the genetic mechanisms leading to its malignant transformation. We expect that the results of the above studies will identify new targets for therapy, which will be eventually tested pre-clinically in our portfolio of genetically defined mouse models of DLBCL.

Public Health Relevance

The goal of the program is to identify new candidate for therapeutic intervention in Diffuse Large B-Cell Lymphoma (DLBCL), the most common human lymphoma. We will use novel technologies for the analysis of normal germinal center B cells from which DLBCL derive, and use these findings to interpret the alterations found in tumors. The results will be validated in mouse models of DLBCL as a pre-clinical testing for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA210105-03
Application #
9528531
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Jhappan, Chamelli
Project Start
2016-08-04
Project End
2023-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Pasqualucci, Laura; Dalla-Favera, Riccardo (2018) Genetics of diffuse large B-cell lymphoma. Blood 131:2307-2319
Brescia, Paola; Schneider, Christof; Holmes, Antony B et al. (2018) MEF2B Instructs Germinal Center Development and Acts as an Oncogene in B Cell Lymphomagenesis. Cancer Cell 34:453-465.e9
Zhang, Jiyuan; Vlasevska, Sofija; Wells, Victoria A et al. (2017) The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma. Cancer Discov 7:322-337