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

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

doi:10.1016/j.stem.2017.11.016

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

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 SunZhike Lu, Xi Jiang, Guido Marcucci, James C. Mulloy, Jianhua Yang, Zhijian Qian, Minjie Wei, Chuan He, Jianjun Chen

Research output: Contribution to journal › Article › peer-review

Abstract

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. 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.

Original language	English (US)
Pages (from-to)	191-205.e9
Journal	Cell Stem Cell
Volume	22
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2017.11.016
State	Published - Feb 1 2018
Externally published	Yes

Keywords

acute myeloid leukemia
HSC
HSPCs
LSCs/LICs
METTL14
MYB
MYC
myeloid differentiation block
N-methyladenosine modification
SPI1

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

Online availability

10.1016/j.stem.2017.11.016

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Cite this

Weng, H., Huang, H., Wu, H., Qin, X., Zhao, B. S., Dong, L., Shi, H., Skibbe, J., Shen, C., Hu, C., Sheng, Y., Wang, Y., Wunderlich, M., Zhang, B., Dore, L. C., Su, R., Deng, X., Ferchen, K., Li, C., ... Chen, J. (2018). METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m⁶A Modification. Cell Stem Cell, 22(2), 191-205.e9. https://doi.org/10.1016/j.stem.2017.11.016

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 2018, 'METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m⁶A Modification', Cell Stem Cell, vol. 22, no. 2, pp. 191-205.e9. https://doi.org/10.1016/j.stem.2017.11.016

@article{76276d597adf40758a2d57434c4a995f,

title = "METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification",

abstract = "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. 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.",

keywords = "acute myeloid leukemia, HSC, HSPCs, LSCs/LICs, METTL14, MYB, MYC, myeloid differentiation block, N-methyladenosine modification, SPI1",

author = "Hengyou Weng and Huilin Huang and Huizhe Wu and Xi Qin and Zhao, {Boxuan Simen} and Lei Dong and Hailing Shi and Jennifer Skibbe and Chao Shen and Chao Hu and Yue Sheng and Yungui Wang and Mark Wunderlich and Bin Zhang and Dore, {Louis C.} and Rui Su and Xiaolan Deng and Kyle Ferchen and Chenying Li and Miao Sun and Zhike Lu and Xi Jiang and Guido Marcucci and Mulloy, {James C.} and Jianhua Yang and Zhijian Qian and Minjie Wei and Chuan He and Jianjun Chen",

note = "We thank Genomics, Epigenomics and Sequencing Core at University of Cincinnati and the Genomic Facility at the University of Chicago for next-generation sequencing. This work was supported in part by the NIH R01 Grants CA214965 (J.C.), CA211614 (J.C.), CA178454 (J.C.), CA182528 (J.C.), R50 CA211404 (M. Wunderlich), and RM1 HG008935 (C. He.); grants 81673475 (M. Wei), 81373427 (M. Wei), and 91440110 (J.Y.) from National Nature Science Foundation of China ; and Academic and Research Committee of Cincinnati Children{\textquoteright}s Hospital Medical Center (J.C.M.). C.He is a Howard Hughes Medical Institute Investigator. J.C. is a Leukemia & Lymphoma Society (LLS) Scholar.",

year = "2018",

month = feb,

day = "1",

doi = "10.1016/j.stem.2017.11.016",

language = "English (US)",

volume = "22",

pages = "191--205.e9",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification

AU - Weng, Hengyou

AU - Huang, Huilin

AU - Wu, Huizhe

AU - Qin, Xi

AU - Zhao, Boxuan Simen

AU - Dong, Lei

AU - Shi, Hailing

AU - Skibbe, Jennifer

AU - Shen, Chao

AU - Hu, Chao

AU - Sheng, Yue

AU - Wang, Yungui

AU - Wunderlich, Mark

AU - Zhang, Bin

AU - Dore, Louis C.

AU - Su, Rui

AU - Deng, Xiaolan

AU - Ferchen, Kyle

AU - Li, Chenying

AU - Sun, Miao

AU - Lu, Zhike

AU - Jiang, Xi

AU - Marcucci, Guido

AU - Mulloy, James C.

AU - Yang, Jianhua

AU - Qian, Zhijian

AU - Wei, Minjie

AU - He, Chuan

AU - Chen, Jianjun

N1 - We thank Genomics, Epigenomics and Sequencing Core at University of Cincinnati and the Genomic Facility at the University of Chicago for next-generation sequencing. This work was supported in part by the NIH R01 Grants CA214965 (J.C.), CA211614 (J.C.), CA178454 (J.C.), CA182528 (J.C.), R50 CA211404 (M. Wunderlich), and RM1 HG008935 (C. He.); grants 81673475 (M. Wei), 81373427 (M. Wei), and 91440110 (J.Y.) from National Nature Science Foundation of China ; and Academic and Research Committee of Cincinnati Children’s Hospital Medical Center (J.C.M.). C.He is a Howard Hughes Medical Institute Investigator. J.C. is a Leukemia & Lymphoma Society (LLS) Scholar.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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. 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.

AB - 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. 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.

KW - acute myeloid leukemia

KW - HSC

KW - HSPCs

KW - LSCs/LICs

KW - METTL14

KW - MYB

KW - MYC

KW - myeloid differentiation block

KW - N-methyladenosine modification

KW - SPI1

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JO - Cell Stem Cell

JF - Cell Stem Cell

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