FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N(6)-Methyladenosine RNA Demethylase.
FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N(6)-Methyladenosine RNA Demethylase.
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DOI：
10.1016/j.ccell.2016.11.017
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发表时间：
2017-01-09
期刊：
影响因子：
50.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Li Z;Weng H;Su R;Weng X;Zuo Z;Li C;Huang H;Nachtergaele S;Dong L;Hu C;Qin X;Tang L;Wang Y;Hong GM;Huang H;Wang X;Chen P;Gurbuxani S;Arnovitz S;Li Y;Li S;Strong J;Neilly MB;Larson RA;Jiang X;Zhang P;Jin J;He C;Chen J
N6-甲基腺苷（m6 A）代表哺乳动物mRNA中最普遍的内部修饰。尽管其在各种基本生物过程中的功能重要性，但m6 A在癌症中的研究有限。在这里，我们表明，FTO，作为一种m6 A脱甲基酶，在急性髓细胞白血病（AML）中起着关键的致癌作用。FTO在具有t（11 q23）/MLL重排、t（15;17）/PML-RARA、FLT 3-ITD和/或NPM 1突变的AML中高度表达。FTO通过降低m6 A在这些mRNA转录物中的水平来调节靶点如ASB 2和RARA的表达，从而增强白血病癌基因介导的细胞转化和白血病发生，并抑制全反式维甲酸（ATRA）诱导的AML细胞分化。总的来说，我们的研究证明了m6 A甲基化和相应蛋白在癌症中的功能重要性，并为白血病的发生和药物反应提供了深刻的见解。Li等人表明，FTO，一种N6-甲基腺苷（m6 A）脱甲基酶，在AML亚型中高度表达，促进白血病发生，并抑制全反式视黄酸诱导的白血病细胞分化。FTO通过降低m6 A水平来调节mRNA靶标如ASB 2和RARA发挥其致癌作用。
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 leukemogensis and drug response. 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.