Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia
Yanli Jin, … , Ruibao Ren, Jingxuan Pan
Yanli Jin, … , Ruibao Ren, Jingxuan Pan
Published September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):3961-3980. https://doi.org/10.1172/JCI85239.
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Research Article Hematology

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

Yanli Jin, Jingfeng Zhou, Fang Xu, Bei Jin, Lijing Cui, Yun Wang, Xin Du, Juan Li, Peng Li, Ruibao Ren, Jingxuan Pan

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Figure 8

PRMT5 inhibition reduces long-term multilineage engraftment of human CML CD34+ cells in NSI mice.

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PRMT5 inhibition reduces long-term multilineage engraftment of human CML...
(A) Human CML CD34+ cells were treated with PJ-68 (25.0 μM) in vitro for 3 days and injected into sublethally irradiated (300 cGy) NSI mice. After 12 weeks, human multilineage engraftment was analyzed by flow cytometry. (B and C) The percentage (B) and the absolute number (C) of human CD45+ cells engrafted in the BM after transplantation of human CML CD34+ cells (1 × 106 cells/mouse) for 12 weeks. (D) The proportion of human CD45+ cells engrafted in the spleen at 12 weeks. (E) qRT-PCR analysis of BCR-ABL mRNA level in CD45+ cells engrafted in BM at 12 weeks. (F) The proportion of engraftment of human CD33, CD34, CD11B, CD14, and CD19 in BM. (G) Representative flow cytometry plots of human CD45 and CD33 expression in mice with cells from 1 of the 2 CML patients (n = 3 for control, n = 4 for PJ-68 treatment, each patient). *P < 0.05, **P < 0.01, ***P < 0.0001, 2-tailed Student’s t test.