GAB1 regulation by FoxO1 and its role in CLL migration and tonic AKT activity: novel therapeutic target. GAB1 is upregulated by FoxO1 during the transition of intraclonal CLL cell subpopulation from CXCR4^dimCD5^bright into CXCR4^brightCD5^dim cells. This increases homing capacity of CXCR4^brightCD5^dim cells and also sustains prosurvival tonic AKT activity. During microenvironmental interactions (reflected in CXCR4^dimCD5^bright cells) GAB1 is involved in signaling from BCR and other cell surface receptors, and subsequent AKT activation represses GAB1 transcription via FoxO1. GAB1 inhibitors impair cell migration, inhibit tonic or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.