The m6A methyltransferase METTL14 promotes oncogenic Kras induced juvenile myelomonocytic leukemia through dysregulating autophagy

The N6-methyladenosine (m6A) modification plays an important role in the pathogenesis of various myeloid malignancies. However, its specific role in RAS mutation-induced myeloid malignancy is incompletely understood. In this study, we found that m6A methyltransferase methyltransferase-like 14 (METTL14) was highly expressed and associated with a shorter survival in a RAS-mutation myeloid malignancy, juvenile myelomonocytic leukemia (JMML). The knockout of METTL14 was revealed to significantly promote hematopoietic stem/progenitor cells (HSPCs) expansion and suppresses disease progression in a Kras^G12D/+ mutation-induced mouse model of JMML. Moreover, knockout of METTL14 reduces hyperproliferation of Kras^G12D/+ HSPCs and suppresses oncogenic Kras^G12D/+-induced myeloid disease in a cell-autonomous manner. Mechanistically, we revealed that the knockout of METTL14 reduced the autophagy levels of HSPCs by suppressing the transcription and translation of autophagy-related genes, such as autophagy-related gene 5 (Atg5) and autophagy-related gene 9 (Atg9a), through m6A modification. Furthermore, we found that the autophagy inhibition through knockout of ATG5 in Kras^G12D/+ mutant mice promoted the expansion of HSPCs and inhibited the progression of leukemia disease, consistent with the phenotypes of knockout of METTL14. Finally, we observed that combined treatment with a m6A inhibitor and a MEK inhibitor synergistically suppressed JMML growth. Collectively, these findings highlight the critical role of METTL14 in JMML tumorigenesis and suggest that m6A modification represents a promising therapeutic target for this disease.