BCR-ABL ACCELERATES C2-CERAMIDE-INDUCED APOPTOSIS

In patients with chronic myeloid leukemia (CML), the neoplastic (BCR-A BL(+)) progenitor cells are characterized by an increased proliferativ e activity, Whether these cells are also resistant to apoptosis and if so, under what conditions remains controversial, We now show that hig hly purified populations of very primitive neoplastic progenitor cells obtained directly from CML patients survive and proliferate in vitro for several weeks in the absence of any added growth factors (except i nsulin), In contrast, purified primary normal progenitors maintained u nder the same conditions die rapidly, Nevertheless, both primary CML c ells and BCR-ABL(+) BAF3 cells show the same dose-dependent sensitivit y to TNF-alpha or ceramide-induced apoptosis as their respective norma l counterparts, In fact, time course studies demonstrated an even fast er onset of apoptosis in ceramide-treated BCR-ABL(+) BAF3 cells as com pared to normal controls, BCR-ABL(+) cells treated with ceramide also showed a rapid and sequential increase in the tyrosine phosphorylation of p210(BCR-ABL), p46-56(SHC) and p120(Cbl), These findings suggest g rowth factor deprivation and treatment with TNF-alpha or ceramide trig ger different initial events both of which can lead to apoptosis in fa ctor-dependent hematopoietic cells, However, in the first case, activa tion of apoptosis is blocked by the basal activity of p210(BCR-ABL), w hereas in the second, the presence of p210(BCR-ABL) appears to acceler ate the onset of apoptosis by a mechanism that may involve an activati on of its kinase function.