Abstract
Chronic lymphocytic leukemia (CLL) presents challenges in treatment despite advancements in targeted therapies, often facing resistance or relapse. Chronic inflammation plays a significant role in CLL biology, with heightened inflammatory responses and immune dysfunction. Elevated levels of inflammatory cytokines support this notion. Activating signaling pathways such as NF-κB, Phosphoinositide 3-kinase delta (PI3Kδ), and MAPK via B-cell receptors and CD40 confers advantages to leukemic lymphocytes. Our research focuses on the proinflammatory protein S100A9 in CLL progression. We previously described that patients with CLL release exosomes containing S100A9 during disease progression, correlating with NF-κB activation. S100A9, known for its role in autoimmune diseases and cancers, modulates the antitumor immune response by influencing myeloid-derived suppressor cells. Receptors for S100A9 include Toll-like receptor 4, receptor for advanced glycation end products, and extracellular matrix metalloproteinase inducer (EMMPRIN). We identified a novel molecular mechanism involving the S100A9-EMMPRIN interaction in CLL using primary cells and an in vivo CLL mouse model (Eμ-TCL1). Additionally, we developed an Eμ-TCL1/S100A9-/- mouse model and explored pharmacological targeting of S100A9 in a patient-derived xenograft model, highlighting S100A9 as a promising therapeutic target in CLL with potential clinical applications.