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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3915-3921
NEOPLASIA
Bcl-2 expression restores the leukemogenic potential of a BCR/ABL
mutant defective in transformation
Maria Cirinnà,
Rossana Trotta,
Paolo Salomoni,
Plamen Kossev,
Mariusz Wasik,
Danilo Perrotti, and
Bruno Calabretta
From the Department of Microbiology and Immunology,
Kimmel Cancer Center, Thomas Jefferson University; the University of
Pennsylvania Medical Center, Department of Pathology and Laboratory
Medicine, Philadelphia, PA; and the Department of Biomedical Sciences,
University of Modena, Italy.
Growth factor-dependent hematopoietic cell lines expressing the
BCR/ABL oncoprotein of the Ph chromosome show growth
factor-independent proliferation and resistance to apoptosis.
Apoptosis resistance of BCR/ABL-expressing cells may depend on enhanced
expression of anti-apoptotic proteins as well as reduced expression
and/or inactivation of pro-apoptotic proteins. Compared to myeloid
precursor 32Dcl3 cells expressing wild type BCR/ABL, cells expressing a BCR/ABL mutant lacking amino acids 176-426 in the BCR domain
(p185 BCR) are susceptible to apoptosis induced by interleukin-3
(IL-3) deprivation. These cells exhibited the hypophosphorylated
apoptotic BAD and markedly reduced levels of Bcl-2. Upon ectopic
expression of Bcl-2, these cells showed no changes in BAD
phosphorylation, but they became apoptosis-resistant and proliferated
in the absence of IL-3, albeit more slowly than cells expressing wild
type BCR/ABL. Moreover, the p185BCR/Bcl-2 double transfectants were
leukemogenic when injected into immunodeficient mice, but Bcl-2
expression did not restore the leukemia-inducing effects of p185BCR
to the levels of wild type BCR/ABL. Leukemic cells recovered from the spleen of mice injected with p185BCR/Bcl-2 cells did not show rearrangements in the Bcl-2 genomic locus, but they exhibited enhanced
proliferation in culture and induced a rapidly fatal disease process
when inoculated in secondary recipient mice. Together, these data
support the importance of anti-apoptotic pathways for BCR/ABL-dependent
leukemogenesis and suggest that Bcl-2 expression promotes secondary
changes leading to a more aggressive tumor phenotype.
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