Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia
Yanli Jin, … , Ruibao Ren, Jingxuan Pan
Yanli Jin, … , Ruibao Ren, Jingxuan Pan
Published October 3, 2016; First 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 7

Pharmacological inhibition of PRMT5 activity decreases the frequency of in vivo CML LSCs.

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Pharmacological inhibition of PRMT5 activity decreases the frequency of ...
(A) The mixture of 2 × 105 BM cells from normal C57BL/6 mice with increasing numbers of CML BM cells (2 × 106, 1 × 106, or 5 × 105) from CML mice receiving IM, PJ-68, or their combination (n = 8 for each cell number) was transplanted into WT C57BL/6 mice irradiated at 550 cGy. Engraftment was monitored by analyzing peripheral blood (PB) every week, and GFP+ cells were detected in PB by flow cytometry. (B) The percentages of GFP+ cells at 16 weeks after transplantation. A percentage of GFP+ cells in PB greater than 0.5% was considered as positive engraftment. ***P < 0.0001, 1-way ANOVA, post hoc intergroup comparisons, Tukey’s test. Control (n = 23), IM (n = 14), PJ-68 (n = 18), PJ-68+IM (n = 22). (C) The frequency of LSCs after treatment is summarized in Table 1.