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.