Loss of PRMT7 reprograms glycine metabolism selectively eradicating leukemia stem cells in CML

Selective elimination of cancer stem-like cells (CSCs) but not normal stem cell counterparts may offer potential for curative therapies in certain types of cancer. Chronic myeloid leukemia (CML) is a simplified and conventional paradigm to study the biology of CSCs. There is an urgent need to identify the regulators uniquely driving leukemia stem cells (LSCs). In this study, we validated the critical roles of protein arginine methyltransferase 7 (PRMT7) in BCR-ABL-driven leukemogenesis. Genetic loss of Prmt7 greatly delayed leukemia development and impaired the self-renewal property of LSCs in CML mice without affecting normal hematopoiesis. The methyltransferase activity of PRMT7 was required for its regulatory effect on LSCs because its blockade by an enzymatic mutant or a specific small-molecule inhibitor JS1310 significantly eliminated LSCs and prolonged the survival of CML mice. PRMT7 inhibition by shRNA or JS1310 treatment reduced the survival and impaired the self-renewal ability of human primary CML CD34+ cells but spared normal CD34+ cells. Mechanistically, PRMT7 reprogramed glycine metabolism and seized a switch to determine the fate of CML LSCs. Dietary deprivation of serine and glycine reduced leukemia burden, and reversed the Prmt7 knockout-mediated reduction of LSC maintenance in CML mice. This is the first report to link histone arginine methylation and glycine metabolism in maintenance of LSCs. PRMT7 may represent a valuable therapeutic target for curative therapy in CML.