美国贝克曼研究所陈建军、佛罗里达大学钱志坚和芝加哥大学何川研究组合作取得一项新成果。他们发现RNA去甲基酶ALKBH5选择性促进急性髓系白血病的发生和癌症干细胞的自我更新。2020年5月12日，国际学术期刊《细胞-干细胞》在线发表了这一成果。

研究人员发现ALKBH5缺失在人类急性髓系白血病（AML）中是罕见的。相反，ALKBH5在AML中存在异常的过表达。此外，其表达增加与AML患者的不良预后相关。研究证明ALKBH5是AML发展和维持所必需的，同时也是白血病干细胞/起始细胞（LSCs / LICs）自我更新所必需的，但对于正常的造血作用并无功能。从机理上讲，ALKBH5通过转录后调控其关键靶标（如TACC3）而在AML中发挥促肿瘤作用，TACC3是各种癌症中与预后相关的癌基因。总的来说，这些发现揭示了ALKBH5在白血病发生和LSC / LIC自我更新/维持中的关键功能，并突出了靶向ALKBH5 / N6-甲基腺嘌呤（m6A）轴的治疗潜能。

据悉，m6A是mRNA中最丰富的内部修饰，其与肿瘤发生有关。作为m6A的去甲基酶，ALKBH5可促进乳腺癌和脑肿瘤的发展。但是，在AML中，ALKBH5经常被删除，这暗示着其抑制肿瘤发生的作用。

附：英文原文

Title: RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

Author: Chao Shen, Yue Sheng, Allen C. Zhu, Sean Robinson, Xi Jiang, Lei Dong, Huiying Chen, Rui Su, Zhe Yin, Wei Li, Xiaolan Deng, Yinhuai Chen, Yueh-Chiang Hu, Hengyou Weng, Huilin Huang, Emily Prince, Christopher R. Cogle, Miao Sun, Bin Zhang, Chun-Wei Chen, Guido Marcucci, Chuan He, Zhijian Qian, Jianjun Chen

Issue&Volume: 2020-05-12

Abstract: N6-methyladenosine (m6A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis.As an m6A demethylase, ALKBH5 has been shown to promote the development of breast cancer andbrain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, weshow 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 AMLand self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential fornormal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AMLby post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings revealcrucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenanceand highlight the therapeutic potential of targeting the ALKBH5/m6A axis.

DOI: 10.1016/j.stem.2020.04.009

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30148-X