KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs.
KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs.
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DOI：
10.1158/2159-8290.cd-20-1459
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发表时间：
2022-03-01
期刊：
影响因子：
28.2
通讯作者：
Blanco MA
中科院分区：
文献类型：
--
作者：
Yan F;Li J;Milosevic J;Petroni R;Liu S;Shi Z;Yuan S;Reynaga JM;Qi Y;Rico J;Yu S;Liu Y;Rokudai S;Palmisiano N;Meyer SE;Sung PJ;Wan L;Lan F;Garcia BA;Stanger BZ;Sykes DB;Blanco MA
表观遗传程序在急性髓细胞白血病（AML）中失调，并有助于加强分化阻滞的致癌状态。为了确定AML细胞命运的关键表观遗传调节因子，我们在AML细胞中进行了以分化为中心的CRISPR筛选。该筛选鉴定了组蛋白乙酰转移酶KAT6A作为髓样分化的新型调节剂，其驱动关键的致白血病基因表达程序。我们发现，KAT6A是一个新描述的转录控制模块，其中KAT6A催化的启动子H3K9ac是由乙酰赖氨酸阅读器ENL，这反过来又与染色质因子的网络合作，以诱导转录延伸的启动子。KAT6A的抑制在体外和体内具有强的抗AML表型，表明KAT6A小分子抑制剂对于AML的单一或组合的基于分化的治疗可能具有高度的治疗意义。
Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene expression programs. We show that KAT6A is the initiator of a newly-described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyllysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small molecule inhibitors could be of high therapeutic interest for mono or combinatorial differentiation-based treatment of AML.
影响因子：
3.8
作者：
Mayer J;Arthur C;Delaunay J;Mazur G;Thomas XG;Wierzbowska A;Ravandi F;Berrak E;Jones M;Li Y;Kantarjian HM
通讯作者：
Kantarjian HM