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

Year: 2025

Type: article

Abstract: 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.

Source: Cell Death and Differentiation

DOI: 10.1038/s41418-025-01561-0