METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism

Li Han; Lei Dong; Keith Leung; Zhicong Zhao; Yangchan Li; Lei Gao; Zhenhua Chen; Jianhuang Xue; Ying Qing; Wei Li; Sheela Pangeni Pokharel; Min Gao; Meiling Chen; Chao Shen; Brandon Tan; Andrew Small; Kitty Wang; Zheng Zhang; Xi Qin; Lu Yang; Mark Wunderlich; Bin Zhang; James C Mulloy; Guido Marcucci; Chun-Wei Chen; Minjie Wei; Rui Su; Jianjun Chen; Xiaolan Deng

doi:10.1016/j.stem.2022.12.006

METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism

Cell Stem Cell. 2023 Jan 5;30(1):52-68.e13. doi: 10.1016/j.stem.2022.12.006.

Authors

Li Han¹, Lei Dong², Keith Leung², Zhicong Zhao³, Yangchan Li⁴, Lei Gao², Zhenhua Chen², Jianhuang Xue⁵, Ying Qing², Wei Li², Sheela Pangeni Pokharel², Min Gao⁶, Meiling Chen⁷, Chao Shen², Brandon Tan², Andrew Small², Kitty Wang², Zheng Zhang², Xi Qin², Lu Yang², Mark Wunderlich⁸, Bin Zhang⁹, James C Mulloy⁸, Guido Marcucci⁹, Chun-Wei Chen¹⁰, Minjie Wei¹¹, Rui Su¹², Jianjun Chen¹³, Xiaolan Deng¹⁴

Affiliations

¹ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
² Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
³ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁴ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
⁵ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
⁶ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
⁷ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
⁸ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁹ City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; Department of Hematologic Malignancies Translational Science, City of Hope, Monrovia, CA 91016, USA.
¹⁰ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
¹¹ School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China. Electronic address: mjwei@cmu.edu.cn.
¹² Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: rsu@coh.org.
¹³ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA. Electronic address: jianchen@coh.org.
¹⁴ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: xideng@coh.org.

Abstract

N⁶-methyladenosine (m⁶A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m⁶A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m⁶A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m⁶A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m⁶A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.

Keywords: AML; BCAA metabolism; BCAT1; BCAT2; LSCs/LICs; METTL16; leukemia stem cells; leukemia-initiating cells; m6A modification; self-renewal.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amino Acids, Branched-Chain / genetics
Amino Acids, Branched-Chain / metabolism
Animals
Carcinogenesis / pathology
Cell Self Renewal*
Humans
Leukemia, Myeloid, Acute* / pathology
Mammals / metabolism
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Neoplastic Stem Cells / pathology
RNA, Messenger / metabolism
Transaminases / genetics
Transaminases / metabolism

Substances

RNA, Messenger
Amino Acids, Branched-Chain
BCAT1 protein, human
Transaminases
METTL16 protein, human
Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding