METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification

Publication date: Available online 28 December 2017
Source:Cell Stem Cell
Author(s): Hengyou Weng, Huilin Huang, Huizhe Wu, Xi Qin, Boxuan Simen Zhao, Lei Dong, Hailing Shi, Jennifer Skibbe, Chao Shen, Chao Hu, Yue Sheng, Yungui Wang, Mark Wunderlich, Bin Zhang, Louis C. Dore, Rui Su, Xiaolan Deng, Kyle Ferchen, Chenying Li, Miao Sun, Zhike Lu, Xi Jiang, Guido Marcucci, James C. Mulloy, Jianhua Yang, Zhijian Qian, Minjie Wei, Chuan He, Jianjun Chen
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 that 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 downregulated 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 and 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 the protein 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.

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Teaser

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.


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