Molecular signaling in BCR-ABL1–positive myeloid progenitors. The phosphorylated Tyr177 residue of BCR serves as a docking site for growth factor receptor-bound protein 2 (GRB2), which binds GRB2-associated binding protein 2 (GAB2), as well as SOS (a guanine-nucleotide exchanger of RAS), resulting in RAS-MAPK activation, which in turn results in BCL-2 gene transcription. Upon phosphorylation by BCR-ABL1, GAB2 recruits phosphatidylinositol 3-kinase (PI3K), which activates AKT. AKT activation results in increased transcription of MYC gene and stabilization of MYC protein via inhibition of its degradation by GSK-3β. BCR-ABL1 also activates STAT5, both directly and indirectly through activation of JAK2 and the SRC kinases HCK and LYN. The end result is the activation of BCL-X gene transcription. By contrast, BCR-ABL1 abrogates the transcription of interferon consensus sequence binding protein (ICSBP) through an unknown mechanism, which releases the ISCBP-mediated inhibition of BCL-2 and BCL-X gene transcription and results in increased survival of myeloid progenitors. The same effect is attained via 12/15-lipoxygenase (12/15-LO), which may either inhibit PDK1 or activate PTEN (both regulators of AKT), thus resulting in increased phosphorylation of ICSBP. The net effect of BCR-ABL1 kinase activation is the promotion of cell proliferation and survival. Pointed arrows indicate direct interactions and/or activation. Blunt-ended arrows indicate inhibitory effects. GSK-3β, glycogen synthase kinase-3β; PIP₃, phosphatidylinositol-3,4,5-triphosphate.