Efficient treatment of acute myeloid leukemia (AML) patients remains a challenge despite recent therapeutic advances. Here, using a CRISPRi screen targeting chromatin factors, we identified the nucleosome-remodeling factor (NURF) subunit BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader domains of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.

中文翻译：

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另一种 NURF 复合物通过调节绝缘体区域的可及性来维持急性髓性白血病


尽管最近的治疗取得了进展，但急性髓性白血病 （AML） 患者的有效治疗仍然是一个挑战。在这里，使用靶向染色质因子的 CRISPRi 筛选，我们确定了核小体重塑因子 （NURF） 亚基 BPTF 是 AML 细胞存活的重要调节因子。我们证明 BPTF 与 SMARCA5 和 BAP18 形成另一种 NURF 染色质重塑复合物，可调节白血病细胞中大量绝缘体区域的可及性。这确保了拓扑相关结构域之间的有效 CTCF 结合和边界形成，这对于维持白血病转录程序至关重要。我们还证明，经过充分研究的 BPTF 的 PHD2-BROMO 染色质读取器结构域虽然有助于复杂地募集到染色质，但对于白血病细胞生长来说是必不可少的。综上所述，我们的结果揭示了替代 NURF 复合物如何导致白血病，并为其靶向 AML 提供了基本原理。