BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Menée sur des modèles murins de myélome multipe, cette étude évalue l'efficacité d'un inhibiteur de protéines associées à la chromatine sur la régulation de l'oncogène c-Myc
MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc. º BET bromodomain proteins regulate MYC transcription º The BET bromodomain inhibitor JQ1 selectively downregulates MYC and Myc-dependent target genes º BRD4 binds to IgH enhancers next to MYC in rearranged multiple myeloma cells º JQ1 inhibits myeloma cell proliferation in clinically relevant models Small-molecule inhibition of chromatin-reading bromodomoain proteins leads to transcriptional downregulation of the oncogene c-Myc, an intervention that is efficacious in mouse models of multiple myeloma.