The m(6)A RNA methyltransferase METTL3/METTL14 promotes leukemogenesis through the mdm2/p53 pathway in acute myeloid leukemia

N6-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA and recent studies have highlighted the importance of m(6)A levels in tumor development. In this study, we investigated the expression of methyltransferase-like 3 (METTL3) and 14 (METTL14), components of the RNA m(6)A methyltransferase complex, in samples from 89 patients with acute myeloid leukemia (AML), and followed the survival of 75 of these patients. Our results show that METTL3 and METTL14 are highly expressed in most of the patients with AML (except those with APL), and high levels of METTL3 and/or METTL14 correlated to shorter survival in the patients. In leukemia cell lines K562 and kasumi-1, both METTL3 and METTL14 promote cell proliferation and cell cycle, and the knockdown of METTL3 and METTL14 inhibits proliferation, and induces apoptosis and differentiation. Notably, the knockdown of METTL3 and METTL14 in K562 cell line leads to several changes in the expression of p53 signal pathway, including the upregulation of p53, cyclin dependent kinase inhibitor 1A (CDKN1A/p21), and downregulation of mdm2. Importantly, the m(6)A level of mdm2 mRNA was significant lower after knock-down of METTL3 and METTL14 examined by m(6)A-RIP and mdm2 qPCR assay, and the half-life of mdm2 under actinomycin-D treatment became shorter. Taken together, our study demonstrates that the lower m(6)A levels of mdm2 mRNA mediated by the knockdown of METTL3 and METTL14 could lead to the low stability of mdm2 mRNA transcripts and low expression of MDM2, in the end, activate p53 signal pathway. Both METTL3 and METTL14 play an oncogenic role in AML by targeting mdm2/p53 signal pathway.