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- Title
Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia.
- Authors
Yanli Jin; Jingfeng Zhou; Fang Xu; Bei Jin; Lijing Cui; Yun Wang; Xin Du; Juan Li; Peng Li; Ruibao Ren; Jingxuan Pan; Jin, Yanli; Zhou, Jingfeng; Xu, Fang; Jin, Bei; Cui, Lijing; Wang, Yun; Du, Xin; Li, Juan; Li, Peng
- 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.
- Subjects
LEUKEMIA treatment; STEM cell treatment; LEUCOCYTOSIS; HEMATOLOGIC malignancies; ANEMIA; PROTEIN metabolism; AMINES; ANIMAL experimentation; ANIMALS; ANTINEOPLASTIC agents; CARRIER proteins; CELL lines; CELL physiology; DRUG therapy; EPITHELIAL cells; GENE expression; GENES; GENETIC techniques; HETEROCYCLIC compounds; MICE; QUINOLINE; RNA; STEM cells; TRANSFERASES; CHRONIC myeloid leukemia; PHARMACODYNAMICS
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 10, p3961
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI85239