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However, disease relapse and progression particularly due to persistent leukemia stem cells (LSCs) remain a big challenge in the clinic. Therefore, validation of the therapeutic vulnerability in LSCs is urgently needed. This study verifies the critical role of protein arginine methyltransferase 1 (PRMT1) in the maintenance of CML LSCs. It is found that PRMT1 promotes the survival and serially plating abilities of human primary CML LSCs. Genetic deletion of <jats:italic>Prmt1<\/jats:italic> significantly delays the leukemogenesis and impairs the self\u2010renewal of LSCs in BCR\u2010ABL<jats:bold>\u2013<\/jats:bold>driven CML mice. PRMT1 regulates LSCs and leukemia development depending on its methyltransferase activity. Pharmacological inhibition of PRMT1 activity by MS023 remarkably eliminates LSCs and prolongs the survival of CML mice. Mechanistical studies reveal that PRMT1 promotes transcriptional activation of ribosomal protein L29 (RPL29) via catalyzing asymmetric dimethylation of histone H4R3 (H4R3me2a) at its gene promoter region. PRMT1 augments the global protein synthesis via RPL29 in CML LSCs. Taken together, the findings provide new evidence that histone arginine methylation modification regulates protein synthesis in LSCs and highlight PRMT1 as a valuable druggable target for patients with CML.<\/jats:p>","DOI":"10.1002\/advs.202308586","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:40:15Z","timestamp":1734050415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["PRMT1 Promotes the Self\u2010renewal of Leukemia Stem Cells by Regulating Protein Synthesis"],"prefix":"10.1002","volume":"12","author":[{"given":"Min","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou 510632 China"},{"name":"Jinan University Institute of Tumor Pharmacology College of Pharmacy Jinan University  Guangzhou 510632 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