ALKBH1-mediated tRNA 5-formylcytidine modification facilitates codon-biased translation and leukemogenesis [Ribosome-seq]

Here, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and required for AML development/maintenance and leukemia stem cell (LSC) self-renewal, but is dispensable for normal hematopoiesis. ALKBH1 plays a pivotal role in regulating mitochondrion structure/functions and facilitating oxidative phosphorylation (OXPHOS) to generate energy for AML cell survival/proliferation. Mechanistically, we uncover that ALKBH1 specifically promotes 5-formylcytidine (f5C) formation in tRNAs to expand tRNA decoding capacity and promote translation of essential targets. This mechanism/phenomenon is termed “epitranscriptomic Midas touch”, which promotes expression of WDR43 and BCL2, two crucial targets of ALKBH1 in AML. ALKBH1 targeting markedly enhances BCL2 inhibitor (Venetoclax)’s efficacy in AML treatment. Collectively, our studies reveal the functional importance of a previously unappreciated signaling (i.e., ALKBH1/tRNA-f5C/WDR43/BCL2) in AML, and highlight the potential of targeting ALKBH1 for cancer therapy. ALKBH1 KD was induced after 4 days treatment with doxycycline (1 ug/ml), then were treated with 100 μg/ml cycloheximide for 7 min at 37 ℃ to prevent translation before standard ribosome profiling protocol.