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

N6-Methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A 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 m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response. •FTO is highly expressed in certain subtypes of AMLs such as MLL-rearranged AML•FTO promotes leukemic oncogene-mediated cell transformation and leukemogenesis•FTO targets a set of genes (e.g., ASB2 and RARA) in AML as an m6A RNA demethylase•The FTO⊣ASB2/RARA axis mediates AML cell growth and (ATRA-induced) differentiation Li et al. show that FTO, an N6-methyladenosine (m6A) demethylase, is highly expressed in subtypes of AML, promotes leukemogenesis, and inhibits all-trans-retinoic acid-induced leukemia cell differentiation. FTO exerts its oncogenic role by regulating mRNA targets such as ASB2 and RARA by reducing their m6A levels.