Role of the BCL 6 Proto Oncogene in B Cell Lymphomas

Project: Research project

Project Details

Description

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 represser 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 STATS 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 STATS in plasma cell
differentiation, determine the cause of constitutive STATS activation in ABC-DLBCL, and study the
tumorigenic potential of a constitutively activated STATS 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
STATS 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 STATS in the genetics and
biology of B cell lymphomas.
StatusFinished
Effective start/end date5/1/002/28/12

ASJC

  • Genetics
  • Molecular Biology
  • Oncology
  • Cancer Research
  • Cell Biology

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