BCR – ABL accelerates C2-ceramide-induced apoptosis

Abstract

In patients with chronic myeloid leukemia (CML), the neoplastic (BCR – ABL⁺) progenitor cells are characterized by an increased proliferative activity. Whether these cells are also resistant to apoptosis and if so, under what conditions remains controversial. We now show that highly 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 insulin). In contrast, purified primary normal progenitors maintained under the same conditions die rapidly. Nevertheless, both primary CML cells and BCR – ABL⁺ BAF3 cells show the same dose-dependent sensitivity to TNF-α or ceramide-induced apoptosis as their respective normal counterparts. In fact, time course studies demonstrated an even faster onset of apoptosis in ceramide-treated BCR – ABL⁺ BAF3 cells as compared 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 growth factor deprivation and treatment with TNF-α or ceramide trigger different initial events both of which can lead to apoptosis in factor-dependent hematopoietic cells. However, in the first case, activation of apoptosis is blocked by the basal activity of p210^{BCR – ABL}, whereas in the second, the presence of p210^{BCR – ABL} appears to accelerate the onset of apoptosis by a mechanism that may involve an activation of its kinase function.