Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance
Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance
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DOI：
10.1182/blood-2013-02-483495
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发表时间：
2014-03-13
期刊：
影响因子：
20.3
通讯作者：
Lessard, Julie A.
中科院分区：
文献类型：
--
作者：
Buscarlet, Manuel;Krasteva, Veneta;Lessard, Julie A.
在哺乳动物中，不同亚基家族的组合组装通过创建不同的多态表面来与调节元件和DNA结合因子相互作用，从而赋予依赖于三磷酸腺苷(ATP)的SWI/SNF样Brg/BRM相关因子(BAF)染色质重塑复合体功能特异性。虽然在生化活性方面是多余的，但核心的ATPase亚基BRG/SMARCA4和BRM/SMARCA2在功能上是不同的，可能有助于复杂的特异性。在这里，我们使用定量蛋白质组学显示，在白血病中表达的BAF复合体是围绕BRG ATPase特异性组装的。此外，利用急性髓系白血病的小鼠模型，我们证明了BRG对于白血病的维持是必不可少的，因为缺乏BRG的白血病细胞迅速发生细胞周期停滞和凋亡。最重要的是，我们发现BRG对于维持免疫表型的长期再生造血干细胞是必不可少的，提示巧妙地靶向BRG在白血病中可能具有有效和特异的治疗效果。
In mammals, combinatorial assembly of alternative families of subunits confers functional specificity to adenosine triphosphate (ATP)-dependent SWI/SNF-like Brg/Brm-associated factor (BAF) chromatin remodeling complexes by creating distinct polymorphic surfaces for interaction with regulatory elements and DNA-binding factors. Although redundant in terms of biochemical activity, the core ATPase subunits, BRG/SMARCA4 and BRM/SMARCA2, are functionally distinct and may contribute to complex specificity. Here we show using quantitative proteomics that BAF complexes expressed in leukemia are specifically assembled around the BRG ATPase. Moreover, using a mouse model of acute myeloid leukemia, we demonstrate that BRG is essential for leukemia maintenance, as leukemic cells lacking BRG rapidly undergo cell-cycle arrest and apoptosis. Most importantly, we show that BRG is dispensable for the maintenance of immunophenotypic long-term repopulating hematopoietic stem cells, suggesting that adroit targeting of BRG in leukemia may have potent and specific therapeutic effects.