title: Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia.
abstract: 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). 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 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 cytoskeletal effector VAV1 and the downstream kinase ERK also in the presence of BCR and CXC chemokine receptor CXCR4 stimulation. Interestingly, targeting the LYN/HS1 axis in vitro leads to the concomitant reduction of cytoskeletal activity, BCR signaling and cell survival in the subset of patients with activated LYN/HS1. In a transplantable mouse model based on the EμTCL1 transgenic mouse, LYN/HS1 signaling inhibition interferes with CLL progression and lymphoid organ infiltration. Thus LYN/HS1 axis marks distinct signaling profiles and cytoskeletal-related features that may represent valuable targets for cytoskeleton-targeted therapeutic intervention in CLL.
authors: Division of Molecular Oncology, Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy.
authors: Elisa
authors: E
authors: ten Hacken
authors: Cristina
authors: C
authors: Scielzo
authors: Maria T S
authors: MT
authors: Bertilaccio
authors: Lydia
authors: L
authors: Scarfò
authors: Benedetta
authors: B
authors: Apollonio
authors: Federica
authors: F
authors: Barbaglio
authors: Kostas
authors: K
authors: Stamatopoulos
authors: Maurilio
authors: M
authors: Ponzoni
authors: Paolo
authors: P
authors: Ghia
authors: Federico
authors: F
authors: Caligaris-Cappio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001798:Blood Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001798:Blood Proteins; C061909:HCLS1 protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib