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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 676-684
Versatility of BCR/ABL-expressing leukemic cells in
circumventing proapoptotic BAD effects
Paolo Salomoni,
Fabrizio Condorelli,
Shawn M. Sweeney, and
Bruno Calabretta
From the Department of Microbiology and Immunology, Kimmel Cancer
Center, Thomas Jefferson University, Philadelphia, PA, and the
Department of Biomedical Sciences, Section of General
Pathology, University of Modena, Modena, Italy.
BAD, the proapoptotic member of the "BH3-only" subfamily of
BCL-2 proteins, is inactivated by phosphorylation at serines 112 and
136 and by sequestration in the cytoplasm where it interacts with
members of the 14-3-3 family. In BCR/ABL-expressing cells, BAD is
constitutively phosphorylated and mainly cytoplasmic, whereas in cells
expressing BCR/ABL mutants unable to protect from apoptosis, BAD is
nonphosphorylated. We show here that both the wild-type (WT) and the
S112A/ S136A double mutant (DM) BAD are more potent inducers of
apoptosis in parental than in BCR/ABL-expressing 32D myeloid precursor
cells. Stable lines of parental cells expressing DM BAD could not be
established and most clones from WT BAD retrovirus-infected parental
cells lost BAD expression. On IL-3 withdrawal from parental 32D cells,
BAD was rapidly dephosphorylated by the serine-threonine phosphatase
1 , and localized in the mitochondria, whereas it remained
phosphorylated and did not localize to the mitochondria in the cohort
of BCR/ABL-expressing cells escaping apoptosis induced by WT BAD.
Moreover, these cells showed high levels of BCL-2 and BCL-XL expression. The cohort of BCR/ABL-expressing cells
resistant to apoptosis induced by DM BAD showed only high levels of
BCL-2 and BCL-XL. These findings suggest that
BCR/ABL-expressing cells are more versatile than normal hematopoietic
progenitors in counteracting the apoptotic potential of BAD, and raise
the possibility that tumor cells activate multiple antiapoptotic
pathways for survival in the face of death-inducing stimuli.
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