Fig. 2.

Possible signaling pathways in CML LSCs. Binding of WNT to the frizzled receptor and LRP as co-receptor and activation of WNT/β-catenin is considered the normal signaling mechanism. However, stabilization and transduction of β-catenin into nucleus by P210^BCRABL1 and stimulation of CD70-CD27 after TKI-therapy may be specific to CML LSCs. Activation of WNT/Ca²⁺/NFAT favors CML LSC resistance to imatinib. Attachment of Hedgehog signaling ligands to the Ptch receptor activates Gli family transcription factors. Induction of PI3K activity by P210^BCRABL1 phosphorylates PIP2 resulting in recruitment of PDK1 which phosphorylates AKT activating mTORC1 and sequesters FOXO transcription factors. TKI-therapy enhances nucleus localization of FOXOs increasing survival of CML LSCs. Activation of JAK/STAT signaling by P210^BCRABL1 also increases survival of CML LSCs