The m6A methyltransferase METTL14 promotes oncogenic Kras induced juvenile myelomonocytic leukemia through dysregulating autophagy
The M6A modification plays an important role in the pathogenesis of various myeloid malignancies. However, its specific role in RAS mutant-induced myeloid malignancy is incompletely understood. In this study, we found that m6A methyltransferase METTL14 was highly expressed and associated with a shorter survival in a RAS-mutant 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 KrasG12D/+ mutant-induced mouse model of JMML. Moreover, knockout of METTL14 reduces hyperproliferation of KrasG12D/+ HSPCs and suppresses oncogenic KrasG12D/+-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 Atg5 and Atg9a, through m6A modification. Furthermore, we found that the autophagy inhibition through knockout of ATG5 in Kras 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 an 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 RNA modification represents a promising therapeutic target for this disease. Overall design: The RNA-seq analysis was performed on Mettl14 fl/fl;Mx1-Cre; KrasLSL G12D/+ Lin-ckit+ cells and the results were analyzed together with our previous sequencing results of Mx1-Cre; KrasLSL G12D/+ mice and wild type mice Lin-ckit+ cells.