Wu Wenqi, Jiang Yanan, Xing Donghui, Zhai Yixin, Sun Huimeng, He Xiang, Luo Kaiping, Xu Pengpeng, Pan Feng, Dong Guolei, Ren Guibing, Zhao Zhigang
Department of Senior ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine. Nankai University, Tianjin, 300192, China.
Cell Death Discov. 2024 May 1;10(1):206. doi: 10.1038/s41420-024-01940-5.
Acute myeloid leukemia (AML) with mixed-lineage leukemia (MLL) gene rearrangements (MLL-r) is an aggressive subtype of blood cancer with dismal prognosis, underscoring the urgent need for novel therapeutic strategies. E1A-binding protein (EP300) and CREB-binding protein (CREBBP) function as essential transcriptional coactivators and acetyltransferases, governing leukemogenesis through diverse mechanisms. Targeting EP300/CREBBP holds great promise for treating leukemia with some certain cytogenetic abnormalities. Here, we demonstrated that EP300 and CREBBP are core epigenetic regulators in the pathogenesis of MLL-r AML through assaying the transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Knocking-out EP300/CREBBP and inhibitor (A-485) treatment depressed the MLL-r cells proliferation, while the MLL wild-type cells remained uninfluenced. We found that the CDK4/RB/E2F axis was downregulated specifically in MLL-r AML cell after A-485 treatment by RNA-seq, western blot and cut-tag analyses. EP300/CREBBP inhibitor selectively exerted potent anti-leukemia activity through blocking the MLL-r-BET complex binding to H3K27Ac modification on critical genes loci, distinct from global histone acetylation. Collectively, our study identified EP300/CREBBP as a critical epigenetic driver of MLL-r leukemia and validated their therapeutic potential through targeting inhibition, offering a promising avenue for improving clinical outcomes in this aggressive leukemia.
伴有混合谱系白血病（MLL）基因重排（MLL-r）的急性髓系白血病（AML）是一种侵袭性血癌亚型，预后不佳，这突出表明迫切需要新的治疗策略。E1A结合蛋白（EP300）和CREB结合蛋白（CREBBP）作为重要的转录共激活因子和乙酰转移酶，通过多种机制调控白血病发生。靶向EP300/CREBBP在治疗某些特定细胞遗传学异常的白血病方面具有很大潜力。在此，我们通过高通量测序转座酶可及染色质分析（ATAC-seq）证明，EP300和CREBBP是MLL-r AML发病机制中的核心表观遗传调节因子。敲除EP300/CREBBP以及用抑制剂（A-485）处理可抑制MLL-r细胞增殖，而MLL野生型细胞则不受影响。我们通过RNA测序、蛋白质免疫印迹和切割标签分析发现，A-485处理后，CDK4/RB/E2F轴在MLL-r AML细胞中特异性下调。EP300/CREBBP抑制剂通过阻断MLL-r-BET复合物与关键基因位点上H3K27Ac修饰的结合，选择性地发挥强大的抗白血病活性，这与整体组蛋白乙酰化不同。总的来说，我们的研究确定EP300/CREBBP是MLL-r白血病的关键表观遗传驱动因子，并通过靶向抑制验证了它们的治疗潜力，为改善这种侵袭性白血病的临床结局提供了一条有前景的途径。
