Targeting S100A9-mediated inflammation: A novel therapeutic approach for CLL Open Access

• Chronic inflammation and immune dysfunction promote CLL by activating NF-κB, PI3Kδ, and MAPK via BCR & CD40 boosting leukemic cell survival.

• Research with in vivo and PDX models, including an Eµ-TCL1/S100A9-/- mouse, supports S100A9 targeting as a CLL therapy.

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 like NF-κB, PI3Kδ, and MAPK via B cell receptors (BCR) and CD40 confers advantages to leukemic lymphocytes. Our research focuses on the pro-inflammatory protein S100A9 in CLL progression. We previously described that CLL patients 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 (MDSCs). Receptors for S100A9 include Toll-like receptor 4 (TLR4), the receptor for advanced glycation end products (RAGE), 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 (PDX) model, highlighting S100A9 as a promising therapeutic target in CLL with potential clinical applications.