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 6

Pharmacological inhibition of PRMT5 activity reduces growth of CML stem cells in mice.

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Pharmacological inhibition of PRMT5 activity reduces growth of CML stem ...
(A) A schematic strategy for testing the efficacy of PJ-68 in combination with IM in a CML mouse model. (B) Kaplan-Meier survival curves of CML mice treated with IM, PJ-68, or their combination. Control (n = 10) versus IM (n = 16), ***P = 0.0003; control versus PJ-68 (25 mg/kg) (n = 8), ***P = 0.0010; control versus PJ-68 (25 mg/kg)+IM (n = 8), ***P = 0.0001; control versus PJ-68 (50 mg/kg) (n = 8), ***P = 0.0002; control versus PJ-68 (50 mg/kg)+IM (n = 8), *** P < 0.0001, log-rank test. (C–G) Bulk leukemia cells and stem/progenitor cells in BM were analyzed by flow cytometry. Control (n = 9), IM (n = 8), PJ-68 (25 mg/kg) (n = 8), PJ-68 (25 mg/kg)+IM (n = 6), PJ-68 (50 mg/kg) (n = 8), PJ-68 (50 mg/kg)+IM (n = 7). (C) GFP+ (leukemia) cells and (D) GFP+ myeloid (Gr-1+Mac-1+) cells in the BM. Results for the GFP+ population in the BM are shown: LSK cells (E), LT-HSCs (F), and ST-HSCs (G). (H) GMPs and (I) CMPs in the BM. *P < 0.05, **P < 0.01, ***P < 0.0001, compared with control; #P < 0.05, ##P < 0.01, PJ-68 compared with PJ-68+IM, 1-way ANOVA, post hoc intergroup comparisons, Tukey’s test.