HS1 loss drives cytoskeletal dysregulation and reduces sensitivity to BTK inhibition in chronic lymphocytic leukemia.

Abstract

Chronic lymphocytic leukemia (CLL) is a B cell malignancy driven by aberrant signaling and microenvironmental support. Cytoskeletal remodeling contributes to these mechanisms, where the hematopoietic protein HS1 appears to play a key role. Thus, we generated C57BL/6 HS1 knockout (HS1KO) mice to assess its impact on lymphocyte development. Young HS1KO mice showed some alterations in B cell maturation and T cell differentiation, which appeared to normalize with age. In double-transgenic Eμ-TCL1-HS1KO mice, combining HS1 loss with the standard Eμ-TCL1 CLL mouse model, we observed a trend of reduction in the CD4/CD8 ratio, and disrupted splenic architecture with loss of follicular organization. Transcriptomic and kinase profiling of the human CLL cell line MEC1, in which HS1 was knocked out (MEC1-HS1KO), revealed a coherent impairment in terms of cell mobility as highlighted by severely impaired migration in 2D and 3D environments, reduced chemotactic responses to CXCL12 and CCL19; deregulation of cytoskeletal, adhesion, and apoptotic pathways; and increased resistance to apoptosis. We posited that these defects could reduce sensitivity to BTK (Bruton's tyrosine kinase) inhibition, a standard therapeutic approach in CLL. Primary CLL cells from the spleen of Eμ-TCL1-HS1KO mice appeared to show reduced sensitivity to ibrutinib, a finding that was also observed in adoptive transfer experiments designed to equalize disease burden. Wild-type mice receiving Eμ-TCL1-HS1KO leukemic cells tend to be more resistant to ibrutinib, particularly in the peripheral blood and spleen. All together, these findings establish HS1 as a potential regulator linking B cell receptor signaling, cytoskeletal remodeling, leukemic progression, and response to therapy, supporting its potential as a biomarker for BTK inhibitor sensitivity.