Key Points

  • GAB1 upregulation in an intraclonal subpopulation of peripheral blood CLL cells leads to tonic AKT activity and increased homing capacity.

  • FoxO1-GAB1-pAKT axis can be targeted therapeutically by novel GAB1 inhibitors alone or in combination with BTK inhibition.

Recirculation of chronic lymphocytic leukemia (CLL) cells between the peripheral blood and lymphoid niches plays a critical role in disease pathophysiology, and inhibiting this process is one of the major mechanisms of action for BCR inhibitors such as ibrutinib or idelalisib. Migration is a complex process guided by chemokine receptors and integrins. However, it remains largely unknown how CLL cells integrate multiple migratory signals while balancing survival in peripheral blood and the decision to return to immune niches. Here we provide evidence for the use of CXCR4/CD5 intraclonal subpopulations to study CLL cells migration regulation. We performed RNA profiling of CXCR4dimCD5bright versus CXCR4brightCD5dim cells and identified differential expression of dozens of molecules with a putative function cell migration. We have shown that GRB2 associated binding protein 1 (GAB1) positively regulates CLL cell homing capacity of CXCR4brightCD5dim cells. Gradual GAB1 accumulation in CLL cells outside immune niches is mediated by FoxO1-based transcriptional GAB1 activation. We also describe that upregulation of GAB1 plays an important role in maintaining basal PI3K activity and "tonic" AKT phosphorylation required to sustain survival of resting CLL cells. This is important during ibrutinib therapy since CLL cells induce the FoxO1-GAB1-pAKT axis, which represents an adaptation mechanism to the inability to home to immune niches. We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors alone or in combination with BTK inhibition. GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit "tonic" or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.

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