Work

ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability

Year: 2026

Type: article

Abstract: Background: Dysregulated mRNA translation is a critical driver of acute myeloid leukemia (AML) progression. However, the mechanisms governing translation elongation during AML progression remain to be elucidated. Here, we aimed to study the role and mechanism of tRNA-U34 methyltransferase ALKBH8 in regulating translation elongation in AML.Methods: ALKBH8 expression levels were analyzed using several independent datasets. Immunoblotting and quantitative polymerase chain reaction were used to evaluate the expression levels of ALKBH8 and other molecules. Knockdown and overexpression were used to evaluate the impact of ALKBH8 on leukemogenic potential in cultured cells, xenografts, and MLL-AF9-driven AML mouse models. Ribosome profiling, RNA sequencing, and tRNA modification analyses were used to determine the effects of ALKBH8 on mRNA translation elongation. Findings: ALKBH8 was found to be overexpressed in AML and correlated with poor patient prognosis. Genetic depletion of ALKBH8 markedly impaired the proliferation and leukemogenic capacity of AML cells both in vitro and in vivo. ALKBH8 mediates the mcm5U modification of tRNAs, facilitating efficient translation elongation. Loss of ALKBH8 induces ribosome pausing and preferentially destabilizes transcripts enriched in adenine-ending codons. ALKBH8 regulates the expression of DNA repair gene BRCA1 in a codon-dependent manner. ALKBH8 depletion sensitizes AML cells to the PARP inhibitor olaparib both in vitro and in vivo. Interpretation: Our study reveals a codon-specific mechanism by which ALKBH8 regulates oncogenic translation in AML and highlights the ALKBH8-BRCA1 axis as a potential therapeutic target.

Source: Cell Reports

DOI: 10.1016/j.celrep.2026.118193