BET inhibition restores NPM1c+-mediated deregulation of chromatin in AML
Acute Myeloid Leukemia is a severe hematological malignancy with poor outcomes in adults and children. Among the most common mutations in AML is a heterozygous mutation in the genenucleophosmin(NPM1), which results in the cytoplasmic translocation of NPM1 protein (NPM1c+) along with several of its interacting partners. Here, we show that several members of the cohesin complex have increased cytoplasmic presence in AML cells that carry the NPM1 mutation. Treatment with BET inhibitors results in decreased levels of NPM1c+, causing activation of cohesin-regulated genes and super enhancers, demonstrating a differential response to BET inhibitors compared to NPM1 wild type cells. In addition, we demonstrate that BETi diminish the levels of ribosomal polysomes, with a putative impact on translation. Our results demonstrate novel promising avenues for the usage of BET inhibitors in therapies to treat AML. Overall design: AML cell line treated with DMSO, JQ1, and OTX015.