NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia.
NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia.
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DOI：
10.1016/j.celrep.2016.02.074
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发表时间：
2016-03-29
期刊：
影响因子：
8.8
通讯作者：
Miller WH Jr
中科院分区：
文献类型：
--
作者：
Nichol JN;Galbraith MD;Kleinman CL;Espinosa JM;Miller WH Jr
驱动分化的基因的转录控制中的扰动是致癌融合蛋白促进白血病的既定范例。从视黄酸（RA）敏感的急性早幼粒细胞白血病（APL）细胞系，我们推导出RA耐药克隆的特点是在转录起始的块，尽管保持野生型PML/RARA表达。我们发现了PML/RARA，核磷蛋白（NPM）和拓扑异构酶II β（TOP 2B）之间的异常相互作用。令人惊讶的是，在这些细胞中的RA刺激导致核小体重塑BRG 1的染色质缔合增强。NPM或TOP 2B的抑制废除了BRG 1募集。此外，当与RA组合时，NPM抑制和靶向BRG 1恢复分化。在这里，我们证明了NPM和BRG 1在阻碍RA分化中的作用，并暗示染色质重塑介导恶性肿瘤的治疗抗性。NPM突变是急性白血病（AML）患者中最常见的遗传变化，因此，我们的模型可能适用于由NPM驱动的其他更常见的白血病。
Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA) sensitive Acute Promyelocytic Leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction between PML/RARA, Nucleophosmin (NPM) and Topoisomerase II Beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA-differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML) therefore, our model may be applicable to other more common leukemias driven by NPM.