Abstract

The main objective of this project is to understand how the BCL-6 gene is regulated and how its functional interaction with the IL-6/STAT3 pathway may contribute to its role in normal B cells and B cell lymphomas. BCL-6 encodes a POZ-zinc finger type transcription repressor that has been thought to repress transcription in vivo by recruiting corepressors SMRT/NCoR/BCoR and NuRD/MTA3. BCL-6 is constitutively expressed at high levels in many diffuse large cell lymphomas (DLBCL) due to genetic alterations that override a negative autoregulatory mechanism governing BCL-6 transcription. In the normal lymphoid system, high level BCL-6 protein is specifically found in B cells within the germinal centers (GC) and BCL-6 function is critical for GC formation. Our recent work indicates that BCL-6 autoregulation works in a SMRT/NCoR/BCoR- and NuRD/MTA3 independent manner. Therefore in Aim 1, we plan to characterize specific chromatin changes involved in BCL-6 autoregulation and identify the novel corepressor used by the BCL-6 protein to regulate its own transcription. Our recent study also uncovered a set of very novel findings indicating that BCL6 is a powerful inhibitor of STAT3 expression/activation, and that STATS is constitutively activated in the activated B cell like DLBCL (ABC-DLBCL) and required for cell proliferation and survival. Thus, experiments in Aim 2 are designed to characterize the functional relationship between BCL6 and STAT3 in plasma cell differentiation, determine the cause of constitutive STAT3 activation in ABC-DLBCL, and study the tumorigenic potential of a constitutively activated STAT3 in vivo. Since ABC-DLBCL is often associated with poor treatment outcome, we also plan to pursue collaborative studies to evaluate the prognostic value of STAT3 activation in primary DLBCL either as a single marker or in combination with BCL6. Our studies should provide valuable information regarding a novel aspect of BCL6's transrepression mechanism and more importantly, further our understanding of the roles played by BCL6 and STAT3 in the genetics and biology of B cell lymphomas. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA085573-06A1
Application #
7095350
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Howcroft, Thomas K
Project Start
2000-05-01
Project End
2011-03-31
Budget Start
2006-06-05
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$344,094
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Alvarez, Mariano J; Shen, Yao; Giorgi, Federico M et al. (2016) Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nat Genet 48:838-47
Mai, Yun; Yu, J Jessica; Bartholdy, Boris et al. (2016) An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL. Blood 128:2797-2807
Zhao, Hongling; Bauzon, Frederick; Bi, Enguang et al. (2015) Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age. J Biol Chem 290:5797-809
Ding, B Belinda; Bi, Enguang; Chen, Hongshan et al. (2013) IL-21 and CD40L synergistically promote plasma cell differentiation through upregulation of Blimp-1 in human B cells. J Immunol 190:1827-36
Huang, Xin; Meng, Bin; Iqbal, Javeed et al. (2013) Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 31:4520-8
Nahar, Rahul; Ramezani-Rad, Parham; Mossner, Maximilian et al. (2011) Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC. Blood 118:4174-8
Duy, Cihangir; Hurtz, Christian; Shojaee, Seyedmehdi et al. (2011) BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 473:384-8
Bi, Enguang; Ye, B Hilda (2010) An expanding job description for bcl6. J Mol Cell Biol 2:5-7
Duy, Cihangir; Yu, J Jessica; Nahar, Rahul et al. (2010) BCL6 is critical for the development of a diverse primary B cell repertoire. J Exp Med 207:1209-21
Peled, Jonathan U; Yu, J Jessica; Venkatesh, Jeganathan et al. (2010) Requirement for cyclin D3 in germinal center formation and function. Cell Res 20:631-46

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