FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase

N-6-Methyladenosine (m(6)A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m(6)A in cancer have been limited. Here we show that FTO, as an m(6)A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m(6)A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m(6)A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.