T细胞急性淋巴细胞白血病（T-ALL）是一种由未成熟胸腺细胞引起的血液恶性肿瘤。与众所周知的致癌转录因子（例如 NOTCH1 和 MYC）不同，染色质重塑因子在 T-ALL 发病机制中的作用尚不清楚。在这里，我们提供了令人信服的证据，证明 SWI/SNF 染色质重塑复合物如何促进人类 T-ALL 发病机制。转录组和 ATAC-Seq 数据集的综合分析显示，与正常 T 细胞相比，T-ALL 患者样本和细胞系中 SMARCA4（SWI/SNF 复合物的亚基之一）高表达。 SMARCA 蛋白功能的丧失导致多种 T-ALL 细胞系的细胞凋亡诱导和生长抑制。 ATAC-Seq 分析显示，在 SMARCA 蛋白功能丧失后，整个基因组的染色质可及性大幅降低。 RUNX1 与 SMARCA4 蛋白相互作用并共同占据相同的基因组区域。重要的是，当 SMARCA 蛋白功能受损时，NOTCH1-MYC 通路主要受到影响，这表明 SWI/SNF 作为一种新的治疗靶点。© 2024。作者，获得 Springer Nature Limited 的独家许可。

T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy arising from immature thymocytes. Unlike well-known oncogenic transcription factors, such as NOTCH1 and MYC, the involvement of chromatin remodeling factors in T-ALL pathogenesis is poorly understood. Here, we provide compelling evidence on how SWI/SNF chromatin remodeling complex contributes to human T-ALL pathogenesis. Integrative analysis of transcriptomic and ATAC-Seq datasets revealed high expression of SMARCA4, one of the subunits of the SWI/SNF complex, in T-ALL patient samples and cell lines compared to normal T cells. Loss of SMARCA protein function resulted in apoptosis induction and growth inhibition in multiple T-ALL cell lines. ATAC-Seq analysis revealed a massive reduction in chromatin accessibility across the genome after the loss of SMARCA protein function. RUNX1 interacts with SMARCA4 protein and co-occupies the same genomic regions. Importantly, the NOTCH1-MYC pathway was primarily affected when SMARCA protein function was impaired, implicating SWI/SNF as a novel therapeutic target.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.