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 Previous Article | Table of Contents | Next Article 
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
By
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.
 |
ABSTRACT |
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.
| |
INTRODUCTION |
NUMEROUS STUDIES HAVE indicated that the
growth, differentiation, and survival of acute myelogenous leukemia
(AML) cells are regulated by intracellular and extracellular signals.
Positive regulators include cyclins, cyclin-dependent kinases (cdk),
growth-stimulatory cytokines, and bcl-2, while negative regulators
include p53 and the retinoblastoma (RB) genes, inhibitory cytokines,
and cdk inhibitors (see Karp1). Most signals that lead to
apoptosis do so by activating interleukin-1 converting enzyme
(ICE)-like proteases termed caspases.2-5
Caspases are synthesized as proenzymes. Cleavage at specific aspartate
residues converts the proenzymes into biologically active cysteine
proteases. The activated caspases abrogate the effect of substrates
that protect cellular integrity, such as the DNA-repair enzyme
poly(ADP-ribose) polymerase (PARP), and thereby induce apoptotic cell
death. The activation of at least one caspase appears to be an
essential step in cellular apoptosis.2-4 Consistent with
this scheme, caspase 3 (CPP32, prICE, or Yama)6-8 has been
found to be involved in leukemia-cell apoptosis induced by cytotoxic
agents such as ara-C,9,10 etoposide,
mitoxantrone,10 and CPT-11.11 In addition,
activation of caspase 3 and, to some extent, caspase 2 (ICH-1)12-16 appears to be necessary to induce apoptosis in
HL-60 myeloid leukemia cells.17 However, the clinical significance of these caspase levels in AML is unknown.
Caspase 2 was isolated from a human fetal cDNA library by screening
with a probe of the mouse ICE-homolog Need-2 gene,12,13 and
the caspase 2 gene has been assigned to chromosome 7q35.18 Its mRNA is alternatively spliced into two mRNA species encoding two
protein products named ICH-1L and
ICH-1S.13 Over expression of ICH-1L
induces apoptosis in several cell types.13,14 Caspase 2 is
activated by cleavage into three fragments that are then further
processed into 18- and 12-kD active
subunits.15,16 Caspase 3 is a cysteine protease homologous
with ICE.6-8 Its gene has been located on chromosome
4q33-q35.118 In vitro data suggest that both
ICE8 and the cytotoxic T-cell product granzyme
B19 cleave CPP32. The cleaved form of caspase 3 consists of
biologically active subunits p17 and p12.6
Given their role in promoting apoptosis, we hypothesized that caspase
levels predict the clinical outcome of AML patients. We therefore
quantitated the concentrations of caspase 2 and 3 in peripheral blood
low-density cells of 185 patients with newly diagnosed AML and
correlated these concentrations with clinical outcome. We found that
high levels of both caspase 2 and 3 predict poor outcome in AML.
| |
MATERIALS AND METHODS |
Subjects.
Between October 1, 1991 and July 15, 1995, 376 patients with newly
diagnosed, untreated AML were admitted to M.D. Anderson Cancer Center.
Peripheral blood samples were obtained from 218 of these patients
before therapy, during routine diagnostic evaluations as part of
protocols approved by the Human Subjects Committee of The University of
Texas M.D. Anderson Cancer Center. Emergency initiation of therapy at
night or on weekends, before samples could be obtained, and the absence
of circulating blasts were the predominant reasons for nonaccrual in
this study. Eight patients opted for no therapy and were excluded from
analysis, and blood samples from 25 patients were not available for
study, leaving a sample size of 185. Clinical data are presented in
Table 1.
Patients received induction therapy consisting of high-dose
ara-C-based regimens combined with idarubicin alone, fludarabine alone, or both, as described previously.20 Filgrastim
(granulocyte colony-stimulating factor [G-CSF]) was given to 152 patients according to existing clinical protocols. Maintenance therapy
was administered for 6 or 12 months and consisted of standard-dose
ara-C alternating with lower-dose versions of the induction regimen, as
previously described.20 All 17 patients with acute
promyelocytic leukemia (APL) received idarubicin and
all-trans-retinoic acid, as reported previously.21
Only one patient underwent allogeneic bone marrow transplantation.
Peripheral blood cells from nine hematologically normal individuals
were used as controls.
Western immunoblotting for detection of caspase and PARP proteins.
All samples were processed immediately after the blood was drawn.
Low-density cells were obtained by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) fractionation. The percentage of blasts in these peripheral blood samples ranged from 0% to 99% (median, 39%). Western immunoblotting was performed using cell lysates (from 5 × 105 cells), as described previously.22-24 Each
gel run included a sample of K562 cells (American Type Culture
Collection [ATCC]; Rockville, MD), two to three samples of peripheral
blood cells from normal individuals, and molecular-weight markers. The
following antibodies were used to detect the relevant proteins:
monoclonal mouse antihuman CPP32, mouse antihuman ICH-1L
(Transduction Laboratories, Lexington, KY), rabbit antihuman cleaved
CPP32, mouse antihuman PARP (Upstate Biotechnology, Lake Placid, NY),
rabbit antihuman CPP32 (generously provided by Dr Donald W. Nicholson,
Merck Frosst Center for Therapeutic Research, Pointe Clair-Dorval,
Quebec, Canada), and mouse antihuman tubulin (Sigma Chemical Co, St
Louis, MO). Normal mouse IgG (Sigma Chemical Co) was used as a control. To confirm detection of CPP32 and ICH-1L (positive
controls), Jurkat and HeLa cell lines (ATCC), respectively, were used;
for the detection of cleaved CPP32 and PARP, 3T3 cells (ATCC) and HeLa
cell nuclear extracts, respectively, were used.
Bound antibody was detected according to the ECL protocol (Amersham
Life Science, Arlington Heights, IL). Chemiluminescence was detected on
X-OMAT AR5 film (Kodak, Rochester, NY). The levels of caspase 2 and
caspase 3 expression were scored by densitometry on both a Personal
Densitometer SI (Molecular Dynamics, Sunnyvale, CA) and an UltraScan XL
(Pharmacia), and scoring by the two densitometers yielded similar
results. The results were then normalized by dividing the numerical
value of a sample's caspase 2 or caspase 3 signal by that of either
the tubulin signal or the signal of the same caspase obtained from the
K562 positive control on the same blot. To insure standardization of
the positive control, all K562 cell protein used was from a single,
large protein preparation aliquoted into a single-use vial as
previously described.25 To insure that the results were
linear for both the amount of protein loaded and the time of exposure,
various titers of K562 protein were analyzed using the same antibodies.
A linear curve was obtained with preparations of 3 × 104 to 5 × 105 cells. Exposures used for
these data are from the linear range.
Cellular fractionation.
To identify the cells responsible for the production of high levels of
caspase protein, we used fresh peripheral blood cells from eight
additional newly diagnosed AML patients in whom greater than 50% of
the leukemic blasts expressed CD33, but not CD3 antigen. We used the
immunomagnetic selection technique as previously
described.26,27 Briefly, low-density peripheral blood cells
were incubated with CD33 monoclonal antibodies (Becton Dickinson, San
Jose, CA) at a concentration of 1 µg/106 cells in
phosphate-buffered saline (PBS) with 0.25% fetal calf serum for 30 minutes at 4°C. The labeled cells were washed three times and
incubated with goat antimouse IgG-conjugated immunomagnetic beads
(Advanced Magnetics, Cambridge, MA) at 4°C for 60 minutes in an
end-over-end rotation at 20:1 bead:cell ratio. Immunomagnetic bead-rosetted cells were removed using a magnetic particle concentrator (Advanced Magnetics), and unrosetted cells remaining in suspension were
harvested by a Pasteur pipette. CD3+ cells were isolated
from these cells using the same method. Caspase 3 protein was detected
in both the CD33+ and CD3+ cells as described
above.
Statistical methods.
Differences in the values of numerical variables between patient
subgroups were tested using the Mann-Whitney-Wilcoxon and Kruskal-Wallis tests.28 Associations or differences between categorical variables were assessed using the Fisher exact test and its
generalizations. Associations between caspase levels and other patient
characteristics were assessed using standard regression methods.
Survival and event-free survival (EFS) were evaluated using
Kaplan-Meier plots, log-rank tests, and their
generalizations.29,30 The effects of covariates such as
age, cytogenetic abnormalities, and caspase levels on survival and EFS
were evaluated using martingale residual plots31 and the
Cox model and its generalizations.29,30,32 A multivariate
Cox model was obtained via backward elimination, with a P value
cutoff of .05. Before the model was derived, martingale residual plots
were used to assess the functional relationship between each numerical
covariate and survival or EFS and the covariate was transformed as
appropriate. Goodness-of-fit was assessed using the Grambsch-Therneau
test.33,34 All computations were performed on a DEC alpha
2100 5/250 system computer (Digital Electronics Corp, Nashua, NH) in
Splus35 and StatXact (Cytel Software Corp, Cambridge, MA),
using the standard Splus functions and the Splus survival package of
Therneau.36
| |
RESULTS |
Levels of uncleaved caspases 2 and 3 in AML peripheral blood
low-density cells.
Both uncleaved caspase 2 and uncleaved caspase 3 were detected in
peripheral blood low-density cells of normal donors, in K562 cells and
in all AML blood samples (Fig 1).
Normalization of caspase levels to K562 and tubulin levels yielded
similar results. Normalized levels of caspase 2 were higher and the
range of caspase 2 expression larger in AML (median, 0.92) than in
normal peripheral blood low-density cells (median, 0.40; P < .001). Likewise, normalized levels of caspase 3 were higher and the
range of caspase 3 expression larger in AML (median, 1.31) than in
peripheral blood mononuclear cells obtained from hematologically normal
donors (median, 0.85; P = .02) (Fig
2). There was no correlation between the caspase levels and either the
percentage of peripheral blood blasts (R2 = .003 for caspase 2; R2 = .011 for caspase
3) or French-American-British (FAB) category.
A separate analysis of immunomagnetic bead-fractionated cells verified
that most of the uncleaved caspase 3 protein was present in the
leukemic (CD33) fraction, not in the T-cell (CD3) fraction in seven of
eight AML samples (Fig 3). These data also indicate that the level of caspase 3 protein per blast varies from
patient to patient. Among the 185 AML patients, neither caspase 2 nor
caspase 3 level differed significantly between patients whose
cytogenetics were favorable [inversion 16, t(8;21), or t(15;17)], intermediate (a diploid karyotype or insufficient metaphases), or poor
[trisomy 8;  5,7; 11q; t(9;22); or miscellaneous
changes]. Uncleaved caspase 2 and uncleaved caspase 3 exhibited a
positive association in that caspase 3 increased as a quadratic
fraction of caspase 2. While this regression was statistically
significant (P = .023), it explained only
R2 = 5.6% of the variability in caspase 3 so the
association was very weak.
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| Fig 1.
Detection of caspase 2 and caspase 3 protein in AML
peripheral blood low-density cells. A representative blot for cells
from 16 of 185 patients is depicted. The lane loaded with protein of
K562 cells is labeled "K562" and the lane loaded with protein
from hematologically normal individuals' peripheral blood cells is
labeled "N." The various protein levels of tubulin (55 kD) and of
the uncleaved forms of caspase 2 (48 kD) and caspase 3 (32 kD) are
depicted.
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| Fig 2.
Box plots of uncleaved caspase 2 (upper panel) and of
uncleaved caspase 3 (lower panel) for normal subjects and AML patients
by cytogenetic category. The normalized levels of both caspases are
depicted. Each box runs from the 25th percentile (X25) to
the 75th percentile (X75), with the median represented by a
horizontal line inside the box. The width of each box is proportional
to  n, where n = number of patients to represent n appropriately.
Each whisker runs from the box to 1.5 multiplied by the interquartile
range, but not beyond the sample maximum or minimum, and points beyond
the whiskers are denoted by dashed lines.
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| Fig 3.
Detection of caspase 3 protein in CD3+ and
CD33+ cells obtained from AML peripheral blood
low-density cells. Data from four of eight patients are depicted.
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Association between uncleaved caspase 2 and 3 levels and clinical
outcome.
Martingale residual plots of each caspase indicated that each had a
possible threshold effect on the excess risk of death. To avoid
searching for "optimal" cut points for these variables, which may
be misleading and typically has associated difficulties in
interpretation, we divided each caspase normalized level into its
lower, middle, and upper third. This methodology ensures nearly equal
samples in each subgroup, avoids the arbitrariness of an "optimal" cut point and is very likely to identify a threshold effect. A similar analysis dividing each variable into four levels using quartiles yielded substantively identical results. Because results for EFS were similar to those for survival, only results for
survival are presented below.
Effect of uncleaved caspase 2 level on survival.
Dividing the caspase 2 distribution into thirds showed that patients
with the highest caspase 2 levels had a slightly poorer overall
survival than patients with caspase 2 levels in the lower two thirds
(data not shown), but this difference was not significant (P = .16). Caspase 2 had a similar effect among patients with favorable or
intermediate cytogenetics and among patients with poor-prognosis
cytogenetics, but neither effect was significant (data not shown).
Effect of uncleaved and cleaved caspase 3 levels on survival.
Patients with uncleaved caspase 3 levels in the highest third (above
1.57) had a worse survival than patients with lower caspase 3 levels
(median survival, 48 v 96 weeks; P = .04)
(Fig 4A). This remained true for patients
whose cytogenetic abnormalities predicted a favorable or intermediate
survival rate (P = .03) (Fig 4B), but not for patients whose
cytogenetic abnormalities predicted a poor outcome (P = .38)
(Fig 4C).
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| Fig 4.
Effect of uncleaved caspase 3 level on AML patient
survival. The plots show Kaplan-Meier survival curves for AML patients
with the lowest, middle, and highest thirds of normalized caspase 3 levels. Data shown are for all patients (lower two thirds, 123 patients; upper one third, 62 patients) (A), for patients with
favorable and intermediate cytogenetic abnormalities (lower two thirds,
67 patients; upper one third, 36 patients) (B), and for patients with
poor cytogenetic markers (lower two thirds, 56 patients; upper one
third, 26 patients) (C).
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To assess the effect of cleaved caspase 3 on survival, we studied its
level in randomly selected samples from 41 of the 185 AML patients and
divided its normalized levels into high ( 15) and low (<15) groups,
as suggested by martingale residual plots that showed a threshold
effect of survival and cleaved caspase 3 level on survival. Three
patients who died during the first 2 weeks of induction chemotherapy
were omitted from this analysis. Patients with high levels of cleaved
caspase 3 had a better survival rate than patients with low levels of
cleaved caspase 3 (Fig 5), but this was
only marginally significant (P = .08).
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| Fig 5.
Effect of cleaved caspase 3 levels on AML patient
survival. The plot shows the Kaplan-Meier survival curve for patients
with high (15) and low (<15) normalized protein levels of cleaved
(17 kD) caspase 3. Data of 27 patients with high and 11 patients with
low normalized levels of cleaved caspase 3 are depicted.
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To confirm that the cleaved caspase 3 detected by our assay was indeed
biologically active, we analyzed randomly selected frozen protein
samples (106 cells each) from 16 of the 185 AML patients.
In two samples we detected high levels of cleaved caspase 3, and in
these two cases, but not in others, we also detected high levels of
cleaved PARP (Fig 6). These data suggest
that a high level of cleaved caspase 3 may be associated with a
favorable prognosis and that lack of activation (cleavage) of the
proenzyme caspase 3 may result in its accumulation.
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| Fig 6.
Detection of caspase 3 and PARP protein in AML peripheral
blood cells. Data from five of 16 AML patients are depicted. The lane
loaded with protein from peripheral blood cells from normal individuals
is labeled "N." Uncleaved (32 kD) and cleaved (17 kD) caspase 3 (A) and uncleaved (116 kD) and cleaved (85 kD) PARP (B) are depicted.
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Interactive effect of uncleaved caspases 2 and 3 levels on survival.
The 31 patients with high levels of both uncleaved caspase 2 and
uncleaved caspase 3, represented by the Kaplan-Meier plot in the upper
right corner of Fig 7, had significantly
worse survival compared with the remaining 154 patients (P < .001). The small sample sizes for high caspase 2 and low caspase 3 levels (n = 11, lower right corner plot of Fig 7) and for low caspase 2 and high caspase 3 levels (n = 10, upper left corner plot of Fig 7) are
an artifact of the joint distribution of these two variables and are
reflected by the wide 95% confidence bands around these Kaplan-Meier
plots. Similar results were obtained for EFS (P = .003; data
not shown).
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| Fig 7.
Interactive effects of caspase 2 and 3 levels on AML
patient survival. The figure shows a matrix of Kaplan-Meier survival
plots for the 3 × 3 = 9 patient subgroups, determined by caspase 2 level (low, intermediate, or high) and caspase 3 level (low,
intermediate, or high). In each plot the abscissa depicts survival in
weeks, and the ordinate depicts survival probability. The dotted lines
in each plot represent 95% confidence bands.
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We also explored possible associations between the normalized levels of
uncleaved caspase 2 and uncleaved caspase 3 and the presence of
antecedent hematologic disorder (AHD), poor performance status, and
complete remission and relapse rates. Among the 16 tests, a significant
association was found between complete remission and low caspase 2 levels (P = .04) and between treatment failure rate and high
caspase 3 levels (P = .046). A separate analysis indicated that
a good EFS rate was associated with low levels of caspase 3 (P = .05) in all patients.
Caspase 2 and 3 as prognostic factors.
Given the strong interactive effect of the two caspases on survival
(Fig 7) and EFS (data not shown), univariate analyses were performed to
ascertain the importance of these caspases as prognostic factors while
also accounting for the effect of other covariates. In addition to the
normalized levels of uncleaved caspase 2 and 3 and the level of caspase
2 and 3 combined, the prognostic impact of other variables previously
shown to be prognostic in AML were evaluated. Prognostic variables for
poor survival that were significant in the univariate analysis were age
>50 years, hemoglobin  7 g/dL, unfavorable cytogenetics, FAB
categories 1 and 2, Zubrod performance status 3, AHD of >2 months
duration, a high level of uncleaved caspase 3, and a high level of
uncleaved caspase 2 and 3 combined. Ninety of the 185 patients (48.6%)
were treated in laminar air-flow rooms, but this had no significant effect on survival (P = .13). The cutoffs for the continuous
variables age, hemoglobin, and AHD were determined from an examination
of preliminary martingale residual plots. Other variables evaluated, but that lacked prognostic significance, were gender, white blood cell
count, platelet count, fibrinogen, serum bilirubin, and serum albumin.
A multivariate analysis using the Cox proportional-hazards model was
performed with all variables that were prognostic in the univariate
analysis. The final model included only age >50 years, unfavorable
cytogenetics, and a high level of uncleaved caspases 2 and 3 combined.
The fitted model is summarized in Table 2.
The interactive term for the two caspases had the largest effect of the
three variables, with an estimated relative risk of 2.49 (95%
confidence interval, 1.59 to 3.90).
| |
DISCUSSION |
Because leukemia cells are believed to acquire a survival advantage and
because caspases 2 and 3 mediate apoptotic cell death, we expected
caspase levels to be low in AML. Conversely, we found that the levels
of both uncleaved caspase 2 and uncleaved caspase 3 were higher in
peripheral blood low-density cells of AML patients than in those of
hematologically normal individuals, suggesting that the caspase pathway
is dysregulated in AML. Because there was no association whatsoever
between the percentage of blasts and either of the two caspase
concentrations, we postulated that either various nonleukemic cells or
AML blasts produce large amounts of caspase 2 and 3. Production of high
levels of caspase 3 is not characteristic of normal myeloid blasts, as
myeloid progenitors produce only low levels of this
protease.37 Similarly, T lymphocytes, constituting most of
the normal peripheral blood low-density cell population, are probably
not the major source of these caspases because caspase levels in normal
low-density cells were lower than those in AML. Furthermore, in seven
of eight samples, high caspase 3 levels were found in the leukemic
fraction, not in the T-cell fraction. Therefore, leukemia cells are
probably the source of high caspase levels. The chromosomal
localizations of the genes encoding these caspases18 do not
appear to be involved in any of the cytogenetic abnormalities detected
in our patients. Therefore, it is unlikely that these cytogenetic
aberrations account for the high levels of either caspase 2 or caspase
3.
High levels of uncleaved caspase 3 were associated with decreased
survival, particularly in patients with a good or intermediate prognosis. Furthermore, low levels of the unprocessed caspase 3 correlated with a better EFS. While signal transducers and activators of transcription might upregulate caspase expression in AML, as recently found in human fibroblasts,38 lack of caspase
processing could increase the level of the uncleaved caspase form. To
test this hypothesis, we measured the level of cleaved caspase 3 protein in 41 randomly selected AML samples and found that its high
level indicated an increased survival rate. Although a relatively small cohort of patients was studied and the results were only marginally significant (P = .08), the data suggest that lack of cleavage and accumulation of the inactive caspase form may account for its high
levels. A similar mechanism may account for the abnormally high levels
of caspase 2.
Cleaved caspase 3 was detected in several AML samples, and in two of 16 cases a high level of cleaved caspase 3 was associated with PARP
cleavage. This suggests that the processed form of caspase 3 may indeed
cleave PARP and abrogate its ability to effect DNA repair,2-4 thus inducing apoptosis in AML. Because we used
AML blood samples obtained at diagnosis, before the initiation of chemotherapy, it is likely that caspase activation was either triggered
by the immune system or spontaneously. Our results, showing various
degrees of caspase activation in several AML low-density cell samples,
agree with those of Banker et al,39 who demonstrated, using
a flow-cytometry-based assay, that diagnostic AML cells expressed
variable degrees of apoptosis that overlapped the control apoptosis
range of normal myeloid cells. Thus, the apoptotic cascade may be
activated without exogenous intervention in AML, which may in turn
indicate leukemia cell chemosensitivity, the ability of the immune
system to eradicate leukemia cells, or both.
While the level of caspase 2 by itself had no prognostic significance,
univariate analyses showed that expression of high levels of both
uncleaved caspases characterized patients with very poor survival.
Furthermore, a multivariate analysis using the Cox proportional-hazards
model showed that high levels of both caspase 2 and 3 had the largest
prognostic effect of all the variables analyzed, including cytogenetic
abnormalities. Thus, caspase 2 is probably involved in the induction of
apoptosis in AML, although it may be activated in a pathway independent
of caspase 3, as previously suggested by Harvey et al.40
The interactive effect of uncleaved caspase 2 and 3 levels on survival
also suggests that caspase 2 is involved in the induction of apoptosis
in AML and that more than one potential apoptotic pathway is not fully activated in AML.
Taken together, our data suggest that regardless of the upstream events
that modulate the caspase pathways, caspase activation or its lack is a
powerful independent predictor of survival in AML.
| |
FOOTNOTES |
Submitted March 7, 1998;
accepted June 11, 1998.
Supported in part by National Cancer Institute Grant No. PO1 CA 55164.
Address reprint requests to Zeev Estrov, MD, Department of
Bioimmunotherapy, Box 302, The University of Texas M.D. Anderson Cancer
Center, 1515 Holcombe Blvd, Houston, TX 77030.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract