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FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase

2016; Cell Press; Volume: 31; Issue: 1 Linguagem: Inglês

10.1016/j.ccell.2016.11.017

1878-3686

Zejuan Li, Hengyou Weng, Rui Su, Xiaocheng Weng, Zhixiang Zuo, Chenying Li, Huilin Huang, Sigrid Nachtergaele, Lei Dong, Chao Hu, Xi Qin, Lichun Tang, Yungui Wang, Gia-Ming Hong, Hao Huang, Xiao Wang, Ping Chen, Sandeep Gurbuxani, Stephen Arnovitz, Yuan Li, Shenglai Li, Jennifer Strong, Mary Beth Neilly, Richard A. Larson, Xi Jiang, Pumin Zhang, Jie Jin, Chuan He, Jianjun Chen,

Epigenetics and DNA Methylation

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.