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.

急性髓系白血病（Acute Myeloid Leukemia, AML）是一类累及成人与儿童的重症血液系统恶性肿瘤，患者整体预后较差。急性髓系白血病最常见的突变类型之一为核仁素（nucleophosmin, NPM1）基因的杂合突变，该突变可导致NPM1蛋白（NPM1c+）及其部分互作伴侣蛋白发生胞质移位。本研究发现，在携带NPM1突变的AML细胞中，黏连蛋白（cohesin）复合物的多个成员的胞质分布丰度显著升高。经BET抑制剂（BET inhibitors）处理后，NPM1c+的蛋白水平显著下调，同时激活了黏连蛋白调控的基因及超级增强子（super enhancers），这表明相较于NPM1野生型细胞，此类突变细胞对BET抑制剂的应答模式存在显著差异。此外，本研究证实BET抑制剂（后文简称BETi）可降低核糖体多聚核糖体（ribosomal polysomes）的水平，推测该变化会对细胞的翻译过程产生影响。本研究结果为采用BET抑制剂治疗AML提供了全新的潜在治疗途径。实验整体设计：使用二甲基亚砜（DMSO）、JQ1及OTX015处理AML细胞系。