The results of our study suggest the following model (Fig. 8): (1) CML stem cells accumulate dipeptide species through the Slc15A2 dipeptide transporter; (2) these internalized dipeptides furnish a nutrient source that leads to the activation of nutrient signalling, including signalling via p38MAPK; (3) p38MAPK-mediated non-canonical phosphorylation of Smad3–Ser208 supports Foxo3a's known function in supporting CML stem cell activity in vivo. Here, SMAD3 is linked to chronic myelogenous leukemia, BCR-ABL1 positive.