NSUN2-FOSB reciprocity facilitates leukemogenesis in an m5C-dependent manner by increasing BCL2L1 expression.

NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications on RNA to regulate mRNA stability. However, its roles in normal hematopoiesis and leukemogenesis remain poorly understood. Here, we show that NSUN2 is markedly upregulated in primary acute myeloid leukemia (AML) patients' samples compared with normal hematopoietic cells. NSUN2 knockdown impaired AML cell proliferation, induced apoptosis, and reduced colony formation. Genetic ablation of Nsun2 in an MLL-AF9-transformed murine AML model substantially impaired leukemia stem cell self-renewal and prolonged overall survival, while sparing normal hematopoiesis, highlighting NSUN2 as a potential therapeutic target. Notably, wild-type NSUN2, but not catalytically inactive mutants, restored leukemia stem cell function and leukemogenesis in NSUN2-deficient AML cells, indicating that these effects are m⁵C-dependent. Mechanistically, NSUN2 stabilized FosB proto-oncogene (FOSB) mRNA via m⁵C modification at nucleotide 3656 in the 3' untranslated region, thereby upregulating FOSB expression. In turn, FOSB transcriptionally activated NSUN2, forming a feedforward regulatory loop. Furthermore, FOSB promoted expression of the anti-apoptotic regulator B-cell lymphoma-2-like protein 1 (BCL2L1) by directly binding to its promoter. In conclusion, these findings uncover a novel NSUN2-FOSB-BCL2L1 axis that drives AML leukemogenesis in an m5C-dependent manner, suggesting the therapeutic potential of targeting this pathway.