Aljedai et al. (2015) found a significant upregulation of Notch1, Notch2 and the Notch-target gene HES1 in the most primitive CD34+Thy+ subset of CML stem cells, suggesting that Notch pathway activation is critical for LSC population expansion. Interestingly, Notch activation results in imatinib resistance due to the activation of the compensatory PI3K-Akt/mTOR pathway, finally resulting in BCR/ABL-positive cells persistence that could be prevented by the combined inhibition of Notch and BCR-ABL (Aljedai et al., 2015). This evidence concerns the gene BCR and chronic myelogenous leukemia, BCR-ABL1 positive.