Abstract

Aggressive non Hodgkin's B-cell lymphomas often carry chromosomal translocations in the proto-oncogene BCL-6 locus. Translocations deregulate BCL-6 expression via promoter substitution, leading to constitutive high levels of the wild type BCL-6 protein in lymphoma B cells. In normal B cells, the BCL-6 protein is expressed only at the germinal center stage. BCL-6 is a zinc finger-containing transcription repressor. Knock out studies in mice have suggested important regulatory functions for BCL-6 in the immune system. Still, very little is known about how its expression is normally regulated in B as well as in non-B cells. In addition, the mechanism by which abnormal BCL-6 expression contributes to lymphomagenesis is still unclear. The first specific aim will attempt to characterize a negative autoregulatory mechanism governing BCL-6 transcription. Experiments are designed to first firmly establish its existence in B cells with a wild type BCL-6 gene. Its integrity in tumor B cells with genetically altered BCL-6 gene will then studied. In the second aim, we will test our hypothesis that continued expression of the BCL-6 protein is essential for maintaining the tumorigenicity of lymphoma cell lines. We will attempt to downregulate the activity of BCL-6 protein by expression of either the antisense or dominant negative BCL-6 mutants (knock down approach). Corresponding changes in the cellular phenotype of lymphoma cells will be studied. As our preliminary data suggests a role of BCL-6 in preventing apoptosis, identifying a link between BCL-6 and apoptosis regulators will be a priority. In the third aim, effort will be made to search for BCL-6 genes genes based upon this knock down approach. A combination of cDNA RDA and the cDNA microarray techniques will be used. The last specific aim is to establish the causative role of BCL-6 in lymphomagenesis in vivo by generating conditional BCL-6 transgenic mice using the cre-lox system. Phenotypes to be analyzed include germinal center enter function, B cell proliferation and tumorigenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085573-02
Application #
6377787
Study Section
Pathology B Study Section (PTHB)
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$324,716
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009095365
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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