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Bcr-Abl Exerts Its Antiapoptotic Effect Against Diverse Apoptotic
Stimuli Through Blockage of Mitochondrial Release of Cytochrome C
and Activation of Caspase-3
Gustavo P. Amarante-Mendes,
Caryn Naekyung Kim,
Linda Liu,
Yue Huang,
Charles L. Perkins,
Douglas R. Green, and
Kapil Bhalla
From the Division of Hematology/Oncology, Department of Medicine,
Winship Cancer Center, Emory University School of Medicine, Atlanta,
GA; and the La Jolla Institute for Allergy & Immunology, San Diego, CA.
Bcr-Abl expression in leukemic cells is known to exert a potent
effect against apoptosis due to antileukemic drugs, but its mechanism
has not been elucidated. Recent reports have indicated that a variety
of apoptotic stimuli cause the preapoptotic mitochondrial release of
cytochrome c (cyt c) into cytosol, which mediates the cleavage and
activity of caspase-3 involved in the execution of apoptosis. Whether
Bcr-Abl exerts its antiapoptotic effect upstream to the cleavage and
activation of caspase-3 or acts downstream by blocking the ensuing
degradation of substrates resulting in apoptosis, has been the focus of
the present studies. In these, we used (1) the human acute myelogenous
leukemia (AML) HL-60 cells that are stably transfected with the
bcr-abl gene (HL-60/Bcr-Abl) and express p185 Bcr-Abl; and (2)
the chronic myelogenous leukemia (CML)-blast crisis K562
cells, which have endogenous expression of p210 Bcr-Abl. Exposure of
the control AML HL-60 cells to high-dose Ara-C (HIDAC),
etoposide, or sphingoid bases (including C2 ceramide, sphingosine, or sphinganine) caused the accumulation of cyt c in the
cytosol, loss of mitochondrial membrane potential (MMP), and increase
in the reactive oxygen species (ROS). These preapoptotic events were
associated with the cleavage and activity of caspase-3, resulting in
the degradation of poly (adenosine diphosphate
[ADP]-ribose) polymerase (PARP) and DNA fragmentation
factor (DFF), internucleosomal DNA fragmentation, and morphologic
features of apoptosis. In contrast, in HL-60/Bcr-Abl and K562 cells,
these apoptotic stimuli failed to cause the cytosolic accumulation of
cyt c and other associated mitochondrial perturbations, as well as the
failure to induce the activation of caspase-3 and apoptosis. While the
control HL-60 cells showed high levels of Bcl-2 and barely detectable
Bcl-xL, HL-60/Bcr-Abl cells expressed high levels of
Bcl-xL and undetectable levels of Bcl-2, a pattern of
expression similar to the one in K562 cells. Bax and caspase-3
expressions were not significantly different between HL-60/Bcr-Abl or
K562 versus HL-60 cells. These findings indicate that Bcr-Abl
expression blocks apoptosis due to diverse apoptotic stimuli upstream
by preventing the cytosolic accumulation of cyt c and other
preapoptotic mitochondrial perturbations, thereby inhibiting the
activation of caspase-3 and execution of apoptosis.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1700-1705
© 1998 by The American Society of Hematology.
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