BCL6 is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCL). In normal development BCL6 is required for B-cells to enter the germinal center stage of differentiation and undergo immunoglobulin affinity maturation. From the mechanistic standpoint BCL6 is a transcriptional repressor of the BTB-Zinc finger family of proteins. BCL6 represses target genes to mediate its biological effects through recruitment of corepressor proteins. In its initial five years this proposal revealed new insights into the transcriptional and biological actions of BCL6. Some highlights include the discovery that BCL6 attenuates DNA damage sensing in normal and malignant B-cells by directly repressing the ATR gene, that BCL6 can biochemically compartmentalize target genes with distinct biological functions so that they can be signaled to independently by environmental stimuli, and that recruitment of the SMRT, N-CoR and BCoR corepressors to the BCL6 BTB domain is required for repression of key checkpoint genes and the survival of DLBCL cells. This latter observation led us to develop a BCL6 inhibitor drug (as per Aim 1 and 3 of the original proposal) that is now in the process of moving to clinical trials. The current version of this proposal will build on some of these leads to more profoundly explore the mechanistic basis of transcriptional programming in normal and malignant B-cells. Specifically, we hypothesize that BCL6 controls many different biological pathways, several of which vary between normal and malignant B-cells, through biochemically distinct mechanisms. We predict that BCL6 can compartmentalize genes by either introducing a specific combination of histone modifications into their promoters alone or in combination with allied transcription factors, or by physically transporting different genes to discrete transcriptional repressor domains in the nuclei of B-cells. We will use a combination of advanced genomics tools to explore these questions. Finally we predict that many of these functionally distinct transcriptional programs regulated by BCL6 through different corepressors play important roles in maintaining various facets of the malignant lymphoma phenotype. We will explore their contribution by systematically depleting these corepressors and studying the biological impact on lymphoma cells in vitro and in vivo. Gene expression profiling will be used to identify the signatures associated with corepressor loss of function. We will submit these signatures to connectivity mapping in order to identify drugs that mimic depletion of each corepressor and will study their potential use as anti-lymphoma agents.

Public Health Relevance

BCL6 is the most commonly involved oncogene in B-cell lymphomas. This proposal explores basic transcriptional mechanisms that mediate the phenotype of diffuse large Bcell lymphomas, and of normal B- cells undergoing immunoglobulin affinity maturation. The focus is translational, with an eye towards harnessing basic observations to improve diagnostic and therapeutic options for lymphoma patients. Along these lines, over the past five years this research led to the development of a rationally designed BCL6 inhibitor drug which is now being translated for use in clinical trials. In its next phase the proposal will expand upon the scientific theme of characterizing and therapeutically targeting transcriptional mechanisms in lymphoma cells, and using the information to learn as well about the normal immune system.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA104348-10
Application #
8676676
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Walker, S R; Liu, S; Xiang, M et al. (2015) The transcriptional modulator BCL6 as a molecular target for breast cancer therapy. Oncogene 34:1073-82
Huang, Chuanxin; Gonzalez, David G; Cote, Christine M et al. (2014) The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers. Cell Rep 8:1497-508
Jiang, Yanwen; Elemento, Olivier (2014) Tracing the roots of cancer evolution. Cancer Discov 4:995-7
Green, Michael R; Vicente-DueƱas, Carolina; Romero-Camarero, Isabel et al. (2014) Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. Nat Commun 5:3904
Huang, Chuanxin; Geng, Huimin; Boss, Isaac et al. (2014) Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation. Blood 123:1012-20
Hatzi, Katerina; Melnick, Ari (2014) Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends Mol Med 20:343-52
De, Subhajyoti; Shaknovich, Rita; Riester, Markus et al. (2013) Aberration in DNA methylation in B-cell lymphomas has a complex origin and increases with disease severity. PLoS Genet 9:e1003137
Hatzi, Katerina; Jiang, Yanwen; Huang, Chuanxin et al. (2013) A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Rep 4:578-88
Beguelin, Wendy; Popovic, Relja; Teater, Matt et al. (2013) EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23:677-92
Sagardoy, Ainara; Martinez-Ferrandis, Jose I; Roa, Sergio et al. (2013) Downregulation of FOXP1 is required during germinal center B-cell function. Blood 121:4311-20

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