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Blood, 15 June 2002, Vol. 99, No. 12, pp. 4540-4546
NEOPLASIA
Expression levels of apoptosis-related proteins predict clinical
outcome in anaplastic large cell lymphoma
Rosita L. ten Berge,
Chris
J. L. M. Meijer,
Danny F. Dukers,
J. Alain Kummer,
Bellinda A. Bladergroen,
Wim Vos,
C. Erik Hack,
Gert J. Ossenkoppele, and
Joost
J. Oudejans
From the Departments of Pathology, Clinical Chemistry,
and Haematology, VU University Medical Center; and Department of
Immunopathology, CLB; both of Amsterdam, The Netherlands.
In vitro studies suggest that resistance to chemotherapy-induced
apoptosis might explain poor response to therapy in fatal cases. Actual
execution of apoptosis depends on proper functioning of effector
caspases, particularly caspase 3, and on the expression levels of
apoptosis-regulating proteins, including Bcl-2 and the recently
identified granzyme B- specific protease inhibitor 9 (PI9). Thus,
high levels of caspase 3 activation should reflect proper functioning
of the apoptosis pathways, resulting in chemotherapy-sensitive neoplastic cells and a favorable prognosis. We tested this hypothesis by quantifying numbers of tumor cells positive for active caspase 3, Bcl-2, and PI9, respectively, in pretreatment biopsies of systemic anaplastic large cell lymphoma (ALCL) patients and by comparing these
numbers with clinical outcome. Activation of caspase 3 in more than 5%
of the tumor cells was strongly correlated with a highly favorable
outcome. High numbers of Bcl-2- and PI9-positive tumor cells were
found to predict unfavorable prognosis. This prognostic effect was
strongly related to anaplastic lymphoma kinase (ALK) status:
ALK-positive ALCL had significantly higher levels of active caspase 3, while high expression of the antiapoptotic proteins Bcl-2 and PI9 was
almost completely restricted to ALK-negative cases. In conclusion, high
numbers of active caspase 3-positive tumor cells predict a highly
favorable prognosis in systemic ALCL patients. Poor prognosis is
strongly related to high numbers of Bcl-2- and PI9-positive neoplastic
cells. These data support the notion that a favorable response to
chemotherapy depends on an intact apoptosis cascade. Moreover, these
data indicate that differences in prognosis between ALK-positive and
ALK-negative ALCL might be explained by differences in expression of
apoptosis-inhibiting proteins.
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