TRMT6/61A-mediated tRNA m1A methylation promotes codon-dependent TAB2 translation and drives AML progression.

Although mRNA modifications and translational regulation have been extensively studied in various cancers, the precise regulatory mechanisms governing N1-methyladenosine (m¹A)-modified tRNAs in acute myeloid leukemia (AML) remain to be elucidated. Here, we reveal a critical oncogenic role of the m¹A methyltransferase complex TRMT6/TRMT61A in leukemogenesis. We observed that TRMT6/TRMT61A is significantly upregulated in AML and predicts a poor prognosis in patients with AML. Functional assays in vitro and in vivo showed that TRMT6/TRMT61A is crucial for maintaining AML cell proliferation, clonogenic potential, and leukemogenesis, and that this function is dependent on its m¹A methyltransferase activity. Mechanistically, TRMT6/TRMT61A mediates m1A modification of tRNAs, thereby increasing the abundance of specific tRNA subsets and enhancing the codon-frequency-dependent translation of TAB2, a key positive regulator of the NF-κB signaling pathway. In summary, our study elucidates the oncogenic mechanism of the TRMT6/TRMT61A-tRNA m¹A-TAB2 axis in AML, providing potential strategies for targeted therapy.