Driver mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in Acute Myeloid Leukemia
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ABSTRACT: Recent evidence suggests that inhibition of BET epigenetic readers may have clinical utility in hematological malignancies. We demonstrate the efficacy of the BET inhibitor I-BET151 across a variety of AML subtypes, and demonstrate that a common core transcriptional program, which is HOX gene-independent, is downregulated in AML subtypes sensitive to I-BET treatment. Focusing on the most common mutation in AML, we present evidence to suggest that wildtype NPM1 has an inhibitory influence on BRD4, which is relieved upon NPM1c mutation and cytosplasmic dislocation. NPM1c mutation allows upregulation of the core transcriptional program facilitating leukemia development, and this program is abrogated by I-BET therapy. Finally, we demonstrate the efficacy of I-BET151 in human cell lines, a unique murine model and in primary patient samples of NPM1c AML. This submission only includes samples from the human cell line.
ORGANISM(S): Homo sapiens
SUBMITTER: Sam Robson
PROVIDER: E-MTAB-1443 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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