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Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic
Leukemia: Correlations With In Vitro and In Vivo Chemoresponses
Shinichi Kitada,
Janet Andersen,
Sophie Akar,
Juan M. Zapata,
Shinichi Takayama,
Stanislaw Krajewski,
Hong-Gang Wang,
Xin Zhang,
Florencia Bullrich,
Carlo M. Croce,
Kanti Rai,
John Hines, and
John
C. Reed
From the Burnham Institute, Cancer Research Center, La Jolla, CA;
Eastern Cooperative Oncology Group, Brookline, MA; The Sidney Kimmel
Cancer Center/Thomas Jefferson University, School of Medicine,
Philadelphia, PA; The Long Island Jewish Medical Center; and the
MetroHealth Medical Center, Case Western Reserve University, Cleveland,
OH.
B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic
disorder caused primarily by defective programmed cell death (PCD), as
opposed to increased cell proliferation. Defects in the PCD pathway
also contribute to chemoresistance. The expression of several
apoptosis-regulating proteins, including the Bcl-2 family proteins
Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the Bcl-2-binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was
evaluated by immunoblotting using 58 peripheral blood B-CLL specimens
from previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1,
Bax, Bak, and Caspase-3 was commonly found in circulating B-CLL cells,
whereas the Bcl-XL and BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1 were strongly correlated with failure to achieve complete remission (CR) after single-agent therapy (fludarabine or chlorambucil)
(P = .001), but the presence of only seven CRs among the 42 patients for whom follow-up data were available necessitates cautious
interpretation of these observations. Higher levels of the
anti-apoptotic protein BAG-1 were also marginally associated with
failure to achieve CR (P = .04). Apoptosis-regulating
proteins were not associated with patient age, sex, Rai stage, platelet
count, hemoglobin (Hb) concentration, or lymph node involvement,
although higher levels of Bcl-2 and a high Bcl-2:Bax ratio were
correlated with high numbers (>105/µL) of
white blood cells (WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss of allelic heterozygosity at
13q14 (P = .04). On the basis of measurements of apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro chemosensitivity data failed to correlate with in vivo clinical response rates (n = 42) and expression of the various
apoptosis-regulating proteins. Although larger prospective studies are
required before firm conclusions can be reached, these studies show the
expression in B-CLLs of multiple apoptosis-regulating proteins and
suggest that the relative levels of some of these, such as Mcl-1, may provide information about in vivo responses to chemotherapy. In vitro
chemosensitivity data, however, do not appear to be particularly useful
in predicting responses in B-CLL.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3379-3389
© 1998 by The American Society of Hematology.
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