sgi-1027 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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.

Topics: 1-Naphthylamine; Aminoquinolines; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enzyme Induction; Female; Fusion Proteins, bcr-abl; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplastic Stem Cells; Protein-Arginine N-Methyltransferases; Pyrimidines; RNA, Small Interfering; STAT5 Transcription Factor; Xenograft Model Antitumor Assays