ALKBH1 drives tumorigenesis and drug resistance via tRNA decoding reprogramming and codon-biased translation.

ABSTRACT: Cancer cells utilize codon-biased translation to fuel tumorigenesis and drug resistance, but underlying mechanisms remain poorly understood. Here, we show ALKBH1 is overexpressed in acute myeloid leukemia (AML) and essential for leukemia stem/initiating cell (LSC/LIC) self-renewal and AML development/maintenance, whereas dispensable for normal hematopoiesis. ALKBH1 enhances mitochondrial assembly/function and oxidative phosphorylation (OXPHOS), crucial for AML survival/proliferation and resistance to venetoclax, a potent BCL2 inhibitor and widely-used first-line targeted therapy for AML in clinic. Mechanistically, ALKBH1 catalyzes 5-formylcytosine (f5C) at tRNA wobble positions, reprograming decoding and facilitating codon-biased translation, a mechanism we term "Epitranslatomic Midas touc

SUBMITTER: Shen C 

PROVIDER: S-EPMC12377461 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature