INNATE IMMUNE RECEPTORS STIMULATION MODULATES CELL DEATH INDUCED BY CHEMOTHERAPEUTICS DRUGS IN CHRONIC LYMPHOCYTIC LEUKEMIA CELLS.

ARROYO DANIELA S; BUSSI CLAUDIO; PIAGGI D'AGOSTINO ANDRÉS; HELLER VIVIANA B; IRIBARREN PABLO; RODRIGUEZ CECILIA M

Congreso; 3er Congreso Iberoamericano Leucemia Linfocítica Crónica; 2018

INTRODUCTION: The treatment of patients with Chronic Lymphocytic Leukemia (CLL) can include chemotherapy, chemoimmunotherapy, or use of agents targeting specific B-lymphocyte pathways (BCR signaling, BCL-2, etc.). However, CLL remains incurable, drug resistance is a major cause of treatment failure and other unknown biologic factors may contribute to treatment failure. Different groups of CLL patients show heterogeneous response to Toll‐like receptor (TLR) 9 stimulation in terms of proliferation and apoptosis, suggesting that additional molecular characterization of functional roles of different TLRs is needed. We previously reported that stimulation of TLR2 promote cell death by inducing autophagy in phagocytes. In cancer, autophagy plays dual roles, acting as a tumor suppressor mechanism and a pro-survival response, promoting tumor growth. In this context, our objective was to study if the stimulation innate immune receptors stimulation, such as TLRs and Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) modulates fludarabine or BCl-2 inhibitor (ABT-199) induced CLL cell death. MATERIALS AND METHODS: Purified blood mononuclear cells (PBMC) isolated from CLL patients were incubated with Fludarabine or ABT-199 in the presence of a TLR2 ligand (Pam3CSK4) or a NOD2 ligand (MDP). Then, cell death was evaluated by flow cytometry and LC3BII expression by western blot. RESULTS: Pam3CSK4 modulated Fludarabine-induced CLL cell death and increased LC3BII expression. Interestingly, this effect was potentiated by co-stimulation with Pams3CSK4 plus Fludarabine. On the other hand, MDP induced similar effects on LC3BII expression and modulated CLL cell death by ABT-199. CONCLUSIONS: These preliminary results suggest that innate receptors may affect autophagy and leukemia cell survival.