Here, the authors show that the lysophospholipase D Gdpd3 maintains self-renewal capacity of CML stem cells by regulating the quiescence, and AKT/mTORC1 and Foxo3a/β-catenin signalling in an oncogene-independent manner. This evidence concerns the gene FOXO3 and chronic myelogenous leukemia, BCR-ABL1 positive.