Transcriptomics,Genomics

Dataset Information

159

RNA-Sequencing analysis of BET inhibitor resistant cell lines


ABSTRACT: Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor activities are important. Using the Eμ-Myc model of B-cell lymphoma we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of pro-apoptotic (Bim) and anti-apoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1-resistance phenotype. These studies provide important information on mechanisms apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Overall design: RNA-Sequencing of JQ1 resistant and sensitive Eμ-Myc cell lines

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Simon J Hogg  

PROVIDER: GSE87050 | GEO | 2016-09-18

SECONDARY ACCESSION(S): PRJNA343310

REPOSITORIES: GEO

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Publications

BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members.

Hogg Simon J SJ   Newbold Andrea A   Vervoort Stephin J SJ   Cluse Leonie A LA   Martin Benjamin P BP   Gregory Gareth P GP   Gregory Gareth P GP   Lefebure Marcus M   Vidacs Eva E   Tothill Richard W RW   Bradner James E JE   Shortt Jake J   Johnstone Ricky W RW  

Molecular cancer therapeutics 20160712 9


Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of  ...[more]

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