Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

Ying Cheng; Zhuying Gao; Tiantian Zhang; Yuhua Wang; Xueqin Xie; Guoqiang Han; Yashu Li; Rong Yin; Yilin Chen; Peipei Wang; Jin Hu; Tong Zhang; Chengli Guo; Jihua Chai; Jing Wang; Manman Cui; Kexin Gao; Weidong Liu; Shuxin Yao; Pengbo Lu; Ziyan Cao; Yanbing Zheng; Jiwei Chang; Zheming Liu; Qibin Song; Weiming Li; Fuling Zhou; Haojian Zhang

doi:10.1016/j.stem.2022.12.003

Decoding m⁶A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

Cell Stem Cell. 2023 Jan 5;30(1):69-85.e7. doi: 10.1016/j.stem.2022.12.003. Epub 2022 Dec 26.

Authors

Ying Cheng¹, Zhuying Gao¹, Tiantian Zhang¹, Yuhua Wang², Xueqin Xie³, Guoqiang Han³, Yashu Li³, Rong Yin⁴, Yilin Chen⁵, Peipei Wang³, Jin Hu³, Tong Zhang³, Chengli Guo², Jihua Chai², Jing Wang², Manman Cui³, Kexin Gao³, Weidong Liu², Shuxin Yao³, Pengbo Lu³, Ziyan Cao³, Yanbing Zheng³, Jiwei Chang², Zheming Liu⁶, Qibin Song⁶, Weiming Li⁵, Fuling Zhou⁴, Haojian Zhang⁷

Affiliations

¹ The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
² The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China.
³ Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
⁴ Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, China.
⁵ Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Cancer Center, Renmin Hospital, Wuhan University, Wuhan, China.
⁷ The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. Electronic address: haojian_zhang@whu.edu.cn.

PMID: 36574771
DOI: 10.1016/j.stem.2022.12.003

Abstract

N⁶-methyladenosine (m⁶A) is a common chemical modification for mammalian mRNA and exhibits high dynamics in various biological processes. However, dynamics of m⁶A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensive m⁶A landscape during acute myeloid leukemia (AML) development and identify PRMT6 as a key for maintaining AML stem cells. We observe an obvious change in m⁶A methylome during leukemogenesis and find that protein arginine methyltransferase PRMT6 and m⁶A reader IGF2BP2 maintain the function of human and murine leukemia stem cells (LSCs). Genetic deletion or pharmacological inhibition of PRMT6 damages AML development and LSC function. Mechanistically, IGF2BP2 stabilizes PRMT6 mRNA via m⁶A-mediated manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2A expression. PRMT6 loss upregulates MFSD2A expression that increases docosahexaenoic acid levels and impairs LSC maintenance. Collectively, our findings reveal a critical role of PRMT6-MFSD2A signaling axis in AML development and provide a therapeutic strategy for targeting LSCs.

Keywords: IGF2BP2; PRMT6; RNA m(6)A; acute myeloid leukemia; leukemia stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Epigenome
Humans
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Lipids
Mammals / metabolism
Mice
Neoplastic Stem Cells / metabolism
Nuclear Proteins / metabolism
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
RNA* / metabolism
RNA, Messenger / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

RNA
RNA, Messenger
Lipids
IGF2BP2 protein, human
RNA-Binding Proteins
PRMT6 protein, human
Nuclear Proteins
Protein-Arginine N-Methyltransferases