Chronic myeloid leukaemia (CML) is caused by a BCR-ABL fusion that generates a constitutively active tyrosine kinase. Although inhibition of tyrosine kinase with imatinib has been used successfully for CML therapy, it does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Naka et al. show that Foxo3a plays an essential role in the maintenance of LICs in CML, and that TGF-β is a critical regulator of Akt activation in LICs and controls Foxo3a localization. They also show that treatment of LICs in human CML with a TGF-β inhibitor impairs their colony-forming ability in vitro. Full story