KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements.
KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements.
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DOI：
10.1038/s41375-020-1001-z
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发表时间：
2021-04
期刊：
影响因子：
11.4
通讯作者：
Yusa K
中科院分区：
文献类型：
--
作者：
Au YZ;Gu M;De Braekeleer E;Gozdecka M;Aspris D;Tarumoto Y;Cooper J;Yu J;Ong SH;Chen X;Tzelepis K;Huntly BJP;Vassiliou G;Yusa K
组蛋白乙酰转移酶（Histone acetyltransferases, HATs）催化乙酰基从乙酰辅酶a转移到组蛋白赖氨酸残基，在多种生物过程的转录调控中发挥核心作用。HAT活性失调可导致包括发育障碍和癌症在内的人类疾病。通过全基因组CRISPR-Cas9筛选，我们确定了MYST家族的几个hat作为急性髓性白血病（AML）的适合基因。在这里，我们研究了赖氨酸乙酰转移酶KAT7在MLL-X基因融合驱动的aml中的重要性。我们发现，KAT7缺失导致H3K14ac和H4K12ac标记的快速和完全缺失，与AML细胞增殖减少、凋亡增加和分化有关。KAT7的乙酰转移酶活性对这些细胞的增殖至关重要。从机制上讲，我们的数据表明，乙酰化组蛋白为mll融合相关的衔接蛋白（如BRD4和AF4）募集到基因启动子提供了一个平台。在KAT7丢失后，这些因子与RNA聚合酶II一起迅速分离出对AML细胞增殖至关重要的几个mll融合靶基因，包括MEIS1、PBX3和SENP6。我们的研究结果表明，KAT7可能是这种预后不良的AML亚型的治疗靶点。
Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukaemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3 and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.
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影响因子：
50.3
作者：
Muntean AG;Tan J;Sitwala K;Huang Y;Bronstein J;Connelly JA;Basrur V;Elenitoba-Johnson KS;Hess JL
通讯作者：
Hess JL
影响因子：
10.5
作者：
Lalonde ME;Avvakumov N;Glass KC;Joncas FH;Saksouk N;Holliday M;Paquet E;Yan K;Tong Q;Klein BJ;Tan S;Yang XJ;Kutateladze TG;Côté J
通讯作者：
Côté J
影响因子：
5.3
作者：
Kueh, Andrew J.;Dixon, Mathew P.;Thomas, Tim
通讯作者：
Thomas, Tim
影响因子：
11.4
作者：
Feng, Yunpeng;Vlassis, Arsenios;Groth, Anja
通讯作者：
Groth, Anja
影响因子：
11.4
作者：
Kitabayashi, I;Aikawa, Y;Ohki, M
通讯作者：
Ohki, M