武汉大学张好建团队的最新研究发现，染色质改变通过KDM4C-ALKBH5-AXL信号轴促进AML白血病干细胞。2020年5月12日，《细胞—干细胞》杂志在线发表了这项成果。

研究人员发现，N⁶-甲基腺苷（m⁶A）去甲基化酶ALKBH5的表达受人类急性髓细胞性白血病（AML）发生过程中染色质状态改变的调节，而ALKBH5是维持白血病干细胞（LSC）功能所必需的，但对于正常的造血作用却是不需要的。从机制上讲，KDM4C通过增加ALKBH5基因座的染色质可及性，降低H3K9me³水平并促进MYB和Pol II募集来调节ALKBH5表达。此外，ALKBH5以m⁶A依赖的方式影响受体酪氨酸激酶AXL的mRNA稳定性。因此，这些发现将染色质状态动态与m ⁶A修饰蛋白的表达调控联系起来，并揭示了ALKBH5在AML中的选择性和关键作用，它可能作为专门靶向LSC的治疗靶标。

据悉，N⁶-甲基腺苷（m⁶A）是哺乳动物mRNA普遍存在的修饰形式，在各种细胞过程中起关键作用。m⁶A修饰蛋白可催化这种可逆修饰。但是，调控这些m⁶A修饰蛋白的潜在机制仍然难以捉摸。

附：英文原文

Title: Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis

Author: Jiazhen Wang, Yicun Li, Peipei Wang, Guoqiang Han, Tiantian Zhang, Jiwei Chang, Rong Yin, Yi Shan, Jin Wen, Xueqin Xie, Mengdie Feng, Qifan Wang, Jin Hu, Ying Cheng, Tong Zhang, Yashu Li, Zhuying Gao, Chengli Guo, Jing Wang, Jianfei Liang, Manman Cui, Kexin Gao, Jihua Chai, Weidong Liu, Hui Cheng, Lei Li, Fuling Zhou, Lingbo Liu, Yi Luo, Shaoguang Li, Haojian Zhang

Issue&Volume: 2020-05-12

Abstract: N6-methyladenosine (m6A) is a commonly present modification of mammalian mRNAs and plays key roles in variouscellular processes. m6A modifiers catalyze this reversible modification. However, the underlying mechanismsby which these m6A modifiers are regulated remain elusive. Here we show that expression of m6A demethylase ALKBH5 is regulated by chromatin state alteration during leukemogenesisof human acute myeloid leukemia (AML), and ALKBH5 is required for maintaining leukemiastem cell (LSC) function but is dispensable for normal hematopoiesis. Mechanistically,KDM4C regulates ALKBH5 expression via increasing chromatin accessibility of ALKBH5 locus, by reducing H3K9me3 levels and promoting recruitment of MYB and Pol II. Moreover,ALKBH5 affects mRNA stability of receptor tyrosine kinase AXL in an m6A-dependent way. Thus, our findings link chromatin state dynamics with expressionregulation of m6A modifiers and uncover a selective and critical role of ALKBH5 in AML that mightact as a therapeutic target of specific targeting LSCs.

DOI: 10.1016/j.stem.2020.04.001

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30140-5