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Title: BCL6 repression of EP300 provides a basis for rational combinatorial therapy in diffuse large B cell lymphomas.      
keywords:
Transcriptome or Gene expression
ID:
PRJNA132935
description:
The BCL6 transcriptional repressor is a critical oncogene in diffuse large B-cell lymphomas (DLBCL). The specific BCL6 inhibitor RI-BPI potently kills DLBCL cells. We find that RI-BPI induces a particular gene expression signature in DLBCL. In order to identify classes of drugs that might synergize with RIBPI we examined the connectivity of this signature and found a strong association with HDAC and Hsp90 inhibitors. This was explained by the discovery that BCL6 directly represses the p300 lysine acetyltransferase and its co-factor BAT3. RI-BPI induced expression of p300 and BAT3, and p300 acetyltransferase activity, resulting in acetylation of p300 targets like p53 and Hsp90. As a consequence, RI-BPI could attenuate Hsp90 chaperone function, similar to the effect of Hsp90 and HDAC inhibitors. Induction of p300 and BAT3 was required for the anti-lymphoma effects of RI-BPI since specific blockade of either protein rescued DLBCL cells from the BCL6 inhibitor. RI-BPI synergistically killed DLBCL cells in combination with HDAC inhibitors (SAHA, TSA and VPA) and Hsp90 inhibitors (17-DMAG and PUH71). The combination of RI-BPI and SAHA, or RI-BPI and PU-H71 potently suppressed or even eradicated human DLBCL in mice. BCL6 repression of EP300 thus provides a basis for rational targeted combinatorial therapy for patients with DLBCL. Overall design: Direct comparison of gene expression levels in DLBCL cell lines after 24hs of treatment with either a Bcl6 inhibitor peptide or control peptide
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA132935
authentication:
none
authorization:
none
ID:
pmid:21041953
dateReleased:
09-21-2010
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • R01 CA155226/CA/NCI NIH HHS/United States

  • R37 GM062437/GM/NIGMS NIH HHS/United States

  • R01-CA104348/CA/NCI NIH HHS/United States

  • K08 CA127353/CA/NCI NIH HHS/United States

  • N01CO12400/CA/NCI NIH HHS/United States

  • R01 CA143032/CA/NCI NIH HHS/United States

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