Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML

Chang Liu; Waiyi Zou; Danian Nie; Shuyi Li; Chen Duan; Min Zhou; Peilong Lai; Shengyong Yang; Sen Ji; Yangqiu Li; Mei Mei; Shilai Bao; Yanli Jin; Jingxuan Pan

doi:10.1016/j.cmet.2022.04.004

Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML

Cell Metab. 2022 Jun 7;34(6):818-835.e7. doi: 10.1016/j.cmet.2022.04.004. Epub 2022 May 3.

Authors

Chang Liu¹, Waiyi Zou², Danian Nie³, Shuyi Li¹, Chen Duan¹, Min Zhou¹, Peilong Lai⁴, Shengyong Yang⁵, Sen Ji⁵, Yangqiu Li⁶, Mei Mei⁷, Shilai Bao⁷, Yanli Jin⁸, Jingxuan Pan⁹

Affiliations

¹ Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, China.
² Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
³ Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
⁴ Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
⁵ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
⁶ Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China.
⁷ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
⁸ Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: yanlijin2014@jnu.edu.cn.
⁹ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. Electronic address: panjx2@mail.sysu.edu.cn.

PMID: 35508169
DOI: 10.1016/j.cmet.2022.04.004

Abstract

Our group has reported previously on the role of various members of the protein arginine methyltransferase (PRMT) family, which are involved in epigenetic regulation, in the progression of leukemia. Here, we explored the role of PRMT7, given its unique function within the PRMT family, in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Genetic loss of Prmt7, and the development and testing of a small-molecule specific inhibitor of PRMT7, showed that targeting PRMT7 delayed leukemia development and impaired self-renewal of LSCs in a CML mouse model and in primary CML CD34⁺ cells from humans without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 resulted in reduced expressions of glycine decarboxylase, leading to the reprograming of glycine metabolism to generate methylglyoxal, which is detrimental to LSCs. These findings link histone arginine methylation with glycine metabolism, while suggesting PRMT7 as a potential therapeutic target for the eradication of LSCs in CML.

Keywords: GLDC; JS1310; PRMT7; chronic myelogenous leukemia; epigenetic; glycine metabolism; leukemia stem cells; self-renewal; survival.

Publication types

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

MeSH terms

Animals
Epigenesis, Genetic
Glycine / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
Leukemia, Myeloid, Acute* / metabolism
Mice
Neoplastic Stem Cells / metabolism
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
Protein-Arginine N-Methyltransferases / therapeutic use

Substances

PRMT7 protein, mouse
Protein-Arginine N-Methyltransferases
Glycine