Sphingosine kinases (SK): key molecules associated with the activation, proliferation and Ibrutinib-induced cell death of chronic lymphocytic leukemia cells

ALMEJUN B; BORGE, M; COLADO A; PODAZA E.; RISNIK D; DE BRASI C; OPPEZZO P; CABREJO M.; FERNÁNDEZ-GRECCO H; BEZARES RF; CRANCO S.; BURGOS R; SÁNCHEZ-AVALOS J; GIORDANO M; - GAMBERALE R

Orlando

Congreso; 57th ASH Meeting; 2015

Sphingosine-1 phosphate (S1P) is a potent bioactive sphingolipid metabolite that mediates several biological functions, including cell proliferation and survival. S1P generation depends on a reaction catalyzed by two isoforms of sphingosine kinases (SKs), SK1 and SK2, and it can be rapidly degraded by intracellular S1P lyases (S1PL). Given that an elevated expression of SKs or a reduced expression of S1PL have been observed in a variety of cancer cells, we evaluated the role of SKs and S1PL in leukemic cells from CLL patients. By quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot we found that leukemic cells from CLL patients express higher SK1 levels compared to B cells from age-matched healthy donors. Increased levels of SK1 mRNA were associated with the poor prognosis markers CD38 and CD49d. Moreover, in vitro and in vivo activated CLL cells were shown to express higher SK1 mRNA levels compared to non-activated counterparts. Finally we observed that the treatment with SKI-II (a SK1/2 inhibitor) at 30-50μM induced leukemic cell death and reduced the expression of the anti-apoptotic protein bcl-2. Interestingly, non-apoptotic doses of SKI-II impaired CLL activation and proliferation and enhanced leukemic cell death induced by fludarabine, bendamustine or ibrutinib. Our data suggest that SKs are key molecules for CLL activation, proliferation and survival and might be novel therapeutic targets for the treatment of CLL.