FoxO1-GAB1 Axis Regulates Homing Capacity and Tonic AKT Activity in Chronic Lymphocytic Leukemia

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 precisely CLL cells regulate their homingintegrate 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.

The Mechanical and Biochemical Environment Controls Cellular Differentiation During Muscle Regeneration

Urodele amphibians like the newt, are able to completely regenerate lost organs and appendages without scarring. Differentiated tissues are considered a reservoir for uncommitted blastema cells that participate in the regeneration of the lost structure. To determine the influence of the extracellular matrix (ECM) on the recruitment of progenitor cells from the skeletal muscle, we immunohistochemically mapped the limb in 3D and found that a transitional ECM rich in hyaluronic acid (HA), tenascin-C (TN) and fibronectin (FN) is dynamically expressed during the early stages of regeneration [1]. Functional in vitro testing of different ECM components on primary muscle cells revealed that HA and TN support myoblast migration, inhibit differentiation and enhance the fragmentation of multinucleate myotubes and production of viable mononucleate myoblasts, cellular behaviors necessary for blastema formation [1]. In contrast, myoblasts plated on matrices that mimic ECM around differentiated muscle (FN, Matrigel and laminin) induced both proliferation and fusion.