Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia.

Elisa ten Hacken, Cristina Scielzo, Maria T S Bertilaccio, Lydia Scarfò, Benedetta Apollonio, Federica Barbaglio, Kostas Stamatopoulos, Maurilio Ponzoni, Paolo Ghia, Federico Caligaris-Cappio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2264-2273
Number of pages10
JournalBlood
Volume121
Issue number12
DOIs
Publication statusPublished - Mar 21 2013

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

ten Hacken, E., Scielzo, C., Bertilaccio, M. T. S., Scarfò, L., Apollonio, B., Barbaglio, F., Stamatopoulos, K., Ponzoni, M., Ghia, P., & Caligaris-Cappio, F. (2013). Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia. Blood, 121(12), 2264-2273. https://doi.org/10.1182/blood-2012-09-457119