TLR2 STIMULATION PROMOTES AUTOPHAGY AND MODULATES FLUDARABINE-INDUCED CELL DEATH IN CHRONIC LYMPHOCYTIC LEUKEMIA CELLS

ARROYO DS; BUSSI C; PERALTA RAMOS JM; RODRIGUEZ CM; IRIBARREN P

Buenos Aires

Congreso; Reunión conjunta de sociedades de Biociencias; 2017

Chronic Lymphocytic Leukemia (CLL) is a disease characterized by the clonal proliferation and accumulation of mature, typically CD5-positive B-cells within the blood, bone marrow, lymph nodes, and spleen. Leukemic transformation is initiated by alterations that impair apoptosis of clonal B-cells. The pathway engaged in programmed cell death involves several Bcl-2 family proteins. Alternatively, Bcl-2?family proteins have antiautophagic function. In this regard, the autophagy response has dual phenotype in cancer depending of the type of tumor cells. This mechanism can be used for prolonging survival, or for cell death, as well. Whereas autophagy response can be regulated by Toll like receptors (TLRs), and these receptors participate in the CLL progressive pathogenesis, we hypothesize that activation of TLR2 should modulate the autophagy response in CLL cells, conditioning and determining proteins and gene expression involved in the CLL pathogenesis. We performed an analysis of LC3B expression to evaluate autophagy induction, in peripheral blood mononuclear cells (PBMC) isolated from CLL-patients. We observed that Pam3CSK4 (TLR2 ligand) increased LC3B II expression in PBMC and when co-culture Pam3CSK4 whit Fludarabin, we observed higher levels of LC3B II compared with Pam3CSK4 alone. Interesting, Pam3CSK4 modulate B-cell death induced by Fludarabin. Moreover, when we used another innate immune receptor agonist, MDP (NOD2 ligand) we observed similar results. These preliminary experiments are being assayed in others CLL patient samples and also, we plan to evaluate cell death using Pam3CSK4 plus ABT-199 (Bcl-2 inhibitor). These preliminary results may provide important clues to define new strategies for leukemia therapy.