title: Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia.
abstract: Imatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34+ cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/β-catenin pathway in CML CD34+ cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Jin
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Bei
authors.initials: B
authors.lastname: Jin
authors.forename: Lijing
authors.initials: L
authors.lastname: Cui
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Ruibao
authors.initials: R
authors.lastname: Ren
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004790:Enzyme Induction; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002227:Carbazoles; C000622395:PJ-68 compound; D011743:Pyrimidines; D034741:RNA, Small Interfering; C581203:SGI-1027; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D015057:1-Naphthylamine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D016044:Fusion Proteins, bcr-abl