4.7 Article

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

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CELL STEM CELL
卷 27, 期 1, 页码 64-+

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CELL PRESS
DOI: 10.1016/j.stem.2020.04.009

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资金

  1. National Institutes of Health (NIH) [R01 CA214965, R01 CA236399, R01 CA243386, R01 CA211614, R01 HL131444, R01 DK107615, RM1 HG008935]
  2. Cancer Center Support Grant from City of Hope National Medical Center [P30CA33572]

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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.

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