Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis
Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis
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致白血病染色质改变通过 KDM4C-ALKBH5-AXL 信号轴促进 AML 白血病干细胞
DOI：
10.1016/j.stem.2020.04.001
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发表时间：
2020-07-02
期刊：
影响因子：
23.9
通讯作者：
Zhang, Haojian
中科院分区：
文献类型：
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作者：
Wang, Jiazhen;Li, Yicun;Zhang, Haojian
n -6-甲基腺苷（m(6)A）是一种常见的哺乳动物mrna修饰，在各种细胞过程中起关键作用。m(6)A改性剂催化这一可逆改性。然而，这些m(6)A修饰因子调控的潜在机制仍然难以捉摸。本研究表明，在人类急性髓性白血病（AML）的白血病发生过程中，m(6)A去甲基化酶ALKBH5的表达受染色质状态改变的调节，ALKBH5是维持白血病干细胞（LSC）功能所必需的，但对正常造血是必不可少的。从机制上讲，KDM4C通过降低H3K9me3水平和促进MYB和Pol II的募集，增加ALKBH5位点的染色质可及性来调节ALKBH5的表达。此外，ALKBH5以m(6) a依赖的方式影响受体酪氨酸激酶AXL mRNA的稳定性。因此，我们的研究结果将染色质状态动态与m(6)A修饰子的表达调节联系起来，并揭示了ALKBH5在AML中的选择性和关键作用，可能作为特异性靶向LSCs的治疗靶点。
N-6-methyladenosine (m(6)A) is a commonly present modification of mammalian mRNAs and plays key roles in various cellular processes. m(6)A modifiers catalyze this reversible modification. However, the underlying mechanisms by which these m(6)A modifiers are regulated remain elusive. Here we show that expression of m(6)A demethylase ALKBH5 is regulated by chromatin state alteration during leukemogenesis of human acute myeloid leukemia (AML), and ALKBH5 is required for maintaining leukemia stem 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 m(6)A-dependent way. Thus, our findings link chromatin state dynamics with expression regulation of m(6)A modifiers and uncover a selective and critical role of ALKBH5 in AML that might act as a therapeutic target of specific targeting LSCs.