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The tRNA Methyltransferase ALKBH8 Promotes Acute Myeloid Leukemia Progression by Regulating Codon-Dependent Gene Expression

ABSTRACT: Dysregulated mRNA translation is a critical driver of acute myeloid leukemia (AML) progression. Although translation initiation has been extensively studied, the mechanisms governing translation elongation during AML progression remain to be elucidated. Here, we show that the RNA methyltransferase ALKBH8 is overexpressed in AML and is associated with poor prognosis. ALKBH8 is required for the proliferation and leukemogenic capacity of human and murine AML cells, both in vitro and in vivo. Mechanistically, ALKBH8 promotes translation-coupled mRNA stabilization through its methyltransferase domain. Loss of ALKBH8 induces ribosome pausing and preferentially destabilizes transcripts enriched in adenine-ending codons. Specifically, ALKBH8 regulates the expression of DNA repair gene BRCA1 in a codon-dependent manner, resulting in enhanced homologous recombination and cell survival. Moreover, ALKBH8 depletion sensitizes AML cells to the PARP inhibitor olaparib both in vitro and in vivo. Collectively, our study reveals a codon-specific mechanism by which ALKBH8 regulates oncogenic translation in AML, highlighting the ALKBH8-BRCA1 axis as a potential target for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286389 | GEO | 2026/09/27

REPOSITORIES: GEO

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ALKBH8-Mediated Codon-Specific Translation Promotes Colorectal Tumorigenesis

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