CXCL12-MEDIATED NF-KAPPAB AND C-JUN ACTIVATION REGULATES INTERLEUKIN 8 PRODUCTION IN HUMAN T-LYMPHOBLASTIC LEUKEMIA

T acute lymphoblastic leukemia (T-ALL) cells arise inside the thymus and, in most cases, migrate to the bone marrow (BM) where proliferate and expand. Thymic and BM microenvironments play a fundamental role in controlling survival, proliferation, and metabolic functions of T- ALL cells. In this study we explored whether BM-derived stroma can modulate in primary T-ALL cells the production of interleukin (IL)-8, a cytokine that contributes to human cancer progression. To this aim, we performed lympho-stromal co-cultures between normal human BM stro- ma and primary T-ALL cells. After co-culture, we isolated T-ALL from BM cells by fluorescence activated cell sorter (FACS) and analyzed them for the presence of IL-8 mRNA. The interaction with BM-stroma induced a significant increase of IL-8 mRNA in leukemic blasts. The functional blockade of CXCL12 receptor, CXCR4, but not TNF or IL-1R, complete- ly impaired IL-8 induction, thus indicating the involvement of CXCL12/CXCR4 axis in the BM-mediated IL-8 production. In addition, treatment of primary T-ALL cells with recombinant SDF-1 induced a significant increased production of IL-8. The induction was specific for IL-8, as IL-1, IL-6, TNF, or IL-10 production was unchanged after CXCL12 treatment. IL-8 increased expression was also confirmed at mRNA level. Finally, we showed that the activation of nuclear factor (NF)-κB and c-Jun, which represents fundamental pathway in the induc- tion of IL-8 gene transcription, was required for the CXCL12-mediated IL-8 production. Our results implicate a novel function for CXCL12 in regulating IL-8 expression in T-ALL through the activation of the NF-kap- paB and c-Jun pathways. We propose that this novel function of CXCL12 in inducing IL-8 production in leukemia cells may be relevant for the expansion of T-ALL inside the BM microenvironments