Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia

"\"\\\"HS1 (Hematopoietic cell-specific Lyn substrate-1) is a cytoskeletal interactor in the B-cell receptor (BCR) signaling pathway whose phosphorylation correlates with prognosis in Chronic Lymphocytic Leukemia (CLL) patients. The differentially phosphorylated sites and the kinases that regulate HS1 activity in CLL remain poorly understood. We demonstrate that HS1 activity is differentially regulated by LYN kinase that, in a sizable subset of patients, phosphorylates HS1 on Tyrosine (Y)397, resulting in its activation. This correlates with increased cytoskeletal functionality in terms of migration, adhesion and F-actin polymerization. In these patients, LYN is also activated on Y396 residue and its inhibition with the Tyrosine Kinase Inhibitor Dasatinib abrogates HS1-Y397 phosphorylation. This results in the reduction of HS1 activation along with that of VAV1 and ERK also in the presence of microenvironmental stimuli including BCR and CXCR4 stimulation. Interestingly, targeting LYN\\\\\\\/HS1 axis in vitro with Dasatinib leads to the concomitant reduction of the cytoskeletal activity, BCR signaling and cell survival in the selected subset of patients with activated LYN\\\\\\\/HS1. Moreover in a transplantable mouse model based on the EμTCL1 transgenic mouse, LYN\\\\\\\/HS1 signaling pharmacological inhibition interferes with CLL progression and lymphoid organ infiltration. These data suggest that the LYN\\\\\\\/HS1 axis marks distinct signaling profiles and cytoskeletal-related features that may represent valuable targets for cytoskeleton-targeted therapeutic intervention in a sizable fraction of CLL patients.. . \\\"\""