CML AND APOPTOSIS - THE CERAMIDE PATHWAY

In patients with Chronic Myeloid Leukemia (CML), the neoplastic (Bcr-A bl+) progenitors are characterised by an increased proliferative activ ity. These cells appear to become resistant to apoptosis following gro wth factor withdraw. We demonstrate that despite this property, Bcr-Ab l transformed cells (primitive hematopoietic progenitors or cell lines ) remains sensitive to apoptosis induced by Ceramides analogues. This effect is dose dependent and occurs faster in transformed cells as com pared to their normal counterparts. In addition to the classical featu res of apoptosis, we observed that Ceramide-treated CML cells display a rapid and sequential activation of the Bcr-Abl and PI3 kinases. We t hen demonstrated the role of the Bcr-Abl kinase activity in the accele rated response observed in CML cells treated by Ceramide. The PI3 kina se seems to be partly involved in the accelerated Phosphatidyl-Serine exposure observed in Bcr-Abl. transformed cells. Finally, we observed that Ceramide-induced apoptosis does not seem to implicate a Bcl2 prot ein modulation. Taken together these results support the hypothesis of at least two independent signaling pathways initiating programmed cel l death: one will be involved in apoptosis mediated by signals such as cytokine-starving is blocked by the Bcr-Abl fusion protein while the other one initiated by Ceramide is accelerated by the Bcr-Abl protein.