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Measurement of spontaneous and therapeutic agent-induced apoptosis with
BCL-2 protein expression in acute myeloid leukemia
DE Banker, M Groudine, T Norwood and FR Appelbaum
Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
We have designed in vitro assays to investigate the possible association
between apoptosis and chemotherapeutic sensitivity in acute myeloid
leukemias (AMLs). Consistent low levels of spontaneous apoptosis were
observed in myeloid cells from normal bone marrow samples, while untreated
cells collected from 56 de novo AML patients showed variable apoptosis.
Control myeloid cells showed increased apoptosis after in vitro treatments
with daunomycin (DNR), cytosine arabinoside (ARA-C), or gamma irradiation
(RAD). Most AML samples showed less treatment-associated apoptosis,
suggesting that apoptosis responses to therapeutic agents may be frequently
attenuated in AML. Certain cytogenetic abnormalities common in AML may
affect apoptosis, as acute promyelocytic leukemia (APL) samples with
t(15;17) karyotypes showed consistently low levels of spontaneous and
treatment-associated apoptosis. Apoptosis assays may provide unique
functional subtyping of AMLs, as other common cytogenetic subsets showed
variable apoptosis. Altered function of two well-characterized regulators
of apoptosis, BCL- 2 and p53, was not entirely responsible for this
variability. A genomic p53 mutation was found in only one AML sample. All
samples that demonstrated the highest BCL-2-positive cell fractions showed
low apoptosis, but reduced apoptosis was seen in both the presence and
absence of BCL-2 overexpression. Finally, data from matched diagnosis and
relapse sample pairs suggest that neither further reduced apoptosis nor
additional BCL-2 overexpression is necessarily associated with disease
progression.
Volume 89,
Issue 1,
pp. 243-255,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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