METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification.
METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification.
复制标题
METTL14 通过 mRNA m(6)A 修饰抑制造血干/祖细胞分化并促进白血病发生
DOI：
10.1016/j.stem.2017.11.016
复制
发表时间：
2018-02-01
期刊：
影响因子：
23.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Weng H;Huang H;Wu H;Qin X;Zhao BS;Dong L;Shi H;Skibbe J;Shen C;Hu C;Sheng Y;Wang Y;Wunderlich M;Zhang B;Dore LC;Su R;Deng X;Ferchen K;Li C;Sun M;Lu Z;Jiang X;Marcucci G;Mulloy JC;Yang J;Qian Z;Wei M;He C;Chen J
N6-甲基腺苷（m6 A）是真核生物信使RNA（mRNA）中最常见的内部修饰，在许多生物过程中起着关键作用。然而，其在正常和恶性造血中的功能仍然是难以捉摸的。在这里，我们报告了m6 A甲基转移酶复合物的关键成分-胃L14的沉默促进正常HSPC和AML细胞的终末髓样分化，并抑制AML细胞存活/增殖。AML的发展/维持和白血病干细胞/起始细胞（LSC/LIC）的自我更新需要L14。从机制上讲，胃L14通过调节其mRNA靶点（例如，MYB和MYC）通过m6 A修饰，而其本身受SPI 1负调控。总的来说，我们的结果揭示了骨髓生成和白血病发生中的SPI 1抑制剂L14-MYB/MYC信号传导轴，并突出了正常和恶性造血中的胃L14和m6 A修饰的关键作用。N6-甲基腺苷（m6 A）修饰在正常和恶性造血中的作用仍然是难以捉摸的。Weng等人报道了m6 A甲基转移酶复合物的关键组分-胃L14在造血/白血病干细胞的自我更新和分化中的重要作用，并揭示了骨髓生成和白血病发生中的SPI 1胃L14-MYB/MYC信号传导轴。
N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here we report METTL14, a key component of the m6A methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21), and is down-regulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells, and inhibits AML cell survival/proliferation. METTL14 is required for development/maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through m6A modification, while itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1⊣METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis, and highlight the critical roles of METTL14 and m6A modification in normal and malignant hematopoiesis. The role of N6-methyladenosine (m6A) modification in normal and malignant hematopoiesis remains elusive. Weng et al. report the essential role of METTL14, a key component of the m6A methyltransferase complex, in self-renewal and differentiation of hematopoietic/leukemic stem cells and reveal the SPI1⊣METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis.
登录
查看更多内容
影响因子：
48
作者：
Linder, Bastian;Grozhik, Anya V.;Olarerin-George, Anthony O.;Meydan, Cem;Mason, Christopher E.;Jaffrey, Samie R.
通讯作者：
Jaffrey, Samie R.
DOI：
10.1084/jem.20050075
发表时间：
2005-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dakic A;Metcalf D;Di Rago L;Mifsud S;Wu L;Nutt SL
通讯作者：
Nutt SL
miR-181 下调后 HOXA-PBX3 同源盒基因特征的上调与细胞遗传学异常 AML 患者的不良预后相关
影响因子：
20.3
作者：
Li, Zejuan;Huang, Hao;Chen, Jianjun
通讯作者：
Chen, Jianjun
DOI：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
50.3
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
通讯作者：
Chen J