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 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/m⁶A axis.

N ⁶ -甲基腺苷（m ⁶ A）是mRNA中最丰富的内部修饰，与肿瘤发生有关。作为一种 m ⁶ A 去甲基化酶，ALKBH5 已被证明可促进乳腺癌和脑肿瘤的发展。然而，在急性髓性白血病 (AML) 中，据报道ALKBH5经常被删除，这意味着肿瘤抑制作用。在这里，我们展示了ALKBH5人类 AML 中的缺失很少见；相反，ALKBH5 在 AML 中异常过度表达。此外，其增加的表达与 AML 患者的不良预后相关。我们证明 ALKBH5 是 AML 的发展和维持以及白血病干细胞/起始细胞 (LSCs/LICs) 的自我更新所必需的，但对于正常造血不是必需的。从机制上讲，ALKBH5 通过转录后调控其关键靶标（如各种癌症中与预后相关的癌基因TACC3 ）在 AML 中发挥肿瘤促进作用。总的来说，我们的研究结果揭示了 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/m ⁶ A 轴的治疗潜力。