RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia
RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia
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RNA 去甲基化酶 ALKBH5 选择性促进急性髓系白血病的肿瘤发生和癌症干细胞自我更新
DOI：
10.1016/j.stem.2020.04.009
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发表时间：
2020-07-02
期刊：
影响因子：
23.9
通讯作者：
Chen, Jianjun
中科院分区：
文献类型：
--
作者：
Shen, Chao;Sheng, Yue;Chen, Jianjun
N-6-甲基腺苷(m(6)A)是mRNA中含量最丰富的内部修饰，与肿瘤的发生密切相关。作为一种m(6)A去甲基酶，ALKBH5已被证明促进乳腺癌和脑肿瘤的发展。然而，在急性髓系白血病(AML)中，ALKBH5被报道经常被缺失，这意味着它具有肿瘤抑制作用。在这里，我们发现ALKBH5缺失在人类AML中很少见；相反，ALKBH5在AML中异常过表达。此外，其高表达与急性髓系白血病患者预后不良相关。我们证明ALKBH5对AML的发展和维持以及白血病干细胞/起始细胞(LSCs/LICs)的自我更新是必需的，但对正常的造血不是必需的。从机制上讲，ALKBH5通过转录后调节其关键靶点如TACC3在AML中发挥促肿瘤作用，TACC3是多种癌症中的预后相关癌基因。总之，我们的发现揭示了ALKBH5在白血病发生和LSC/LIC自我更新/维持中的关键作用，并强调了靶向ALKBH5/m(6)A轴的治疗潜力。
N-6-methyladenosine (m(6)A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m(6)A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential for normal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AML by post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings reveal crucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenance and highlight the therapeutic potential of targeting the ALKBH5/m(6)A axis.