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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3090-3097
Caspase 2 and Caspase 3 Protein Levels as Predictors of Survival
in Acute Myelogenous Leukemia
Zeev Estrov,
Peter F. Thall,
Moshe Talpaz,
Elihu H. Estey,
Hagop
M. Kantarjian,
Michael Andreeff,
David Harris,
Quin Van,
Monika Walterscheid, and
Steven M. Kornblau
From the Departments of Bioimmunotherapy, Hematology, and
Biomathematics, The University of Texas M.D. Anderson Cancer Center,
Houston, TX.
Because caspase activation is an essential step in programmed cell
death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by
caspase 2 and caspase 3, we hypothesized that caspase 2 and 3 levels
predict clinical outcome in acute myelogenous leukemia (AML). Using
quantitative Western blot analysis, we studied the levels of
nonactivated (uncleaved) caspase 2 and 3 in peripheral blood
low-density cells from 185 patients with newly diagnosed AML. We also
measured the level of activated (cleaved) caspase 3 in 41 randomly
selected samples from the 185 patients. Finally, we analyzed the effect
of caspase 2 and 3 levels and other prognostic variables on patient
survival using a multivariate Cox model. We found that median levels of
nonactivated caspase 2 and 3 were higher in AML than in normal
peripheral blood cells (P < .001 and P <.02,
respectively). There was no association between caspase level and
either the percentage of peripheral blasts or any specific type of
leukemia cell cytogenetic abnormalities. When the effect of each
uncleaved caspase was considered individually, a high level of
uncleaved caspase 3 (P = .04), but not of caspase 2 (P = .16), was associated with decreased survival.
Conversely, a high level of cleaved caspase 3 denoted improved survival
and correlated with the inactivation of the DNA-repair enzyme
poly(ADP-ribose) polymerase. Thus, cleaved caspase 3 could stimulate
the apoptotic cascade further, and lack of its activation likely caused
an accumulation of the uncleaved caspase. Although uncleaved caspase 2 level per se had no prognostic significance, the interactive effect of
high levels of both uncleaved caspase 2 and 3 denoted very poor
survival (P < .001) and had the largest effect of all
prognostic variables (P < .001; estimated relative risk,
2.49; 95% confidence interval, 1.59 to 3.90). Taken together, caspase
2 and caspase 3 protein levels obtained at diagnosis may constitute a
reliable prognostic factor in AML.
© 1998 by The American Society of Hematology.
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