Unknown

Dataset Information

0

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/?-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.

SUBMITTER: Jin Y 

PROVIDER: S-EPMC5096815 | BioStudies | 2016-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC4997248 | BioStudies
2017-01-01 | S-EPMC5564781 | BioStudies
2018-01-01 | S-EPMC5965294 | BioStudies
2015-01-01 | S-EPMC4388554 | BioStudies
2014-01-01 | S-EPMC4151200 | BioStudies
2020-01-01 | S-EPMC7515845 | BioStudies
2014-01-01 | S-EPMC4216903 | BioStudies
2014-01-01 | S-EPMC4226710 | BioStudies
2013-01-01 | S-EPMC3568121 | BioStudies
2020-01-01 | S-EPMC7441008 | BioStudies