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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3717-3721
Cellular Vascular Endothelial Growth Factor Is a Predictor of
Outcome in Patients With Acute Myeloid Leukemia
By
Alvaro Aguayo,
Elihu Estey,
Hagop Kantarjian,
Taghi Mansouri,
Cristi Gidel,
Michael Keating,
Francis Giles,
Zeev Estrov,
Bart Barlogie, and
Maher Albitar
From the Departments of Leukemia and Laboratory Medicine, the
University of Texas MD Anderson Cancer Center, Houston, TX; and the
University of Arkansas for Medical Sciences, Little Rock, AR.
 |
ABSTRACT |
Vascular endothelial growth factor (VEGF) is a potent mitogen for
vascular endothelial cells. It has been associated with angiogenesis,
growth, dissemination, metastasis, and poor outcome in solid tumors. To
assess cellular VEGF levels and their prognostic significance in newly
diagnosed acute myeloid leukemia (AML), we used a radioimmunoassay
(RIA) to quantify VEGF levels in stored samples obtained before
treatment from 99 patients with newly diagnosed AML treated at the MD
Anderson Cancer Center from 1996 to 1998. Outcome in the 99 patients
was representative of that observed in all patients seen at this
institution with this diagnosis during these years, but the 99 patients
had higher white blood cell (WBC) and blast counts than the other
patients. Results of the RIA were confirmed by Western blot. There was
a relationship between increasing VEGF levels and shorter survival
(P = .01), as well as shorter disease-free survival, both
from start of treatment and from complete response (CR) date. In
contrast, there was no relationship between VEGF level and WBC or blast
count, or between VEGF level and such established prognostic factors as
age, cytogenetics, performance status, or presence of an antecedent
hematologic disorder, and multivariate analysis indicated that VEGF was
still prognostic for the above outcomes after accounting for these
factors, as well as treatment. Our results suggest that at least in AML
patients with higher WBC and blast counts, cellular VEGF level is an
independent predictor of outcome.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
VASCULAR ENDOTHELIAL growth factor (VEGF)
is a 34- to 42-kD dimeric multifunctional glycoprotein
with a 15% to 25% homology with platelet-derived growth factor
(PDGF).1,2 The gene for human VEGF is located on chromosome
6p21.3.3 It contains 8 exons and 7 introns.4
Several isoforms of VEGF have been described including 121-, 165-, 189-, and 206-amino acid forms.4 The 165-amino acid isoform
appears to be the most common.5 VEGF is a potent mitogen
for endothelial cells isolated from arteries, veins, and lymphatics.
Overexpression of VEGF is associated with increased
angiogenesis,6-11 growth, invasion, and metastasis in solid
tumors.12-17 Furthermore, correlations have been reported between higher VEGF levels and poor prognosis in solid
tumors.18-21
VEGF was originally cloned from the leukemic cell line
HL60,22 but the role of VEGF and the role of angiogenesis
in leukemia have received only limited attention. Perez-Atayde et
al23 observed heightened angiogenesis in the marrow in
pediatric acute lymphoid leukemia and increased concentrations of basic
fibroblast growth factor (bFGF), a mediator of angiogenesis, in
patients with this disease. Fiedler et al24 found VEGF
transcription in 23 of 33 (69%) patients with acute myeloid leukemia
(AML). Leukemic cell cultures from 24 of these patients produced
significantly higher VEGF levels than CD34-enriched cell cultures
obtained from normal volunteer donors.24
The purpose of this study was to examine the prognostic significance of
cellular VEGF levels in newly diagnosed AML.
| |
PATIENTS AND METHODS |
Patients and controls.
Pretreatment cellular VEGF concentrations were measured in peripheral
blood and marrow samples obtained from 99 patients with newly diagnosed
AML treated at the MD Anderson Cancer Center between 1996 and 1998. Samples were obtained at presentation and stored at  70°C
until analysis. Samples were used if blasts comprised more than 70% of
the mononuclear cells. VEGF was measured in blasts from 34 peripheral
blood samples and 65 bone marrow samples. In 9 patients, VEGF was
measured in both bone marrow and peripheral blood blasts.
Table 1 compares the 99 patients with the
other 167 patients treated here for newly diagnosed AML in the 1996 to
1998 period in whom samples were not stored. The study group had higher
WBC and blast cell counts, leading to the decision to store the
samples. Reflecting these higher counts, the study group more
frequently had inv(16), but the 2 groups were similar with regard to
other standard prognostic factors such as age, performance status,
history of abnormal blood counts (AHD) (hemoglobin <12 g/dL, platelet
count <150 × 109/L, neutrophil count <1.5 × 109/L, or WBC >20 × 109/L) for  1
month before diagnosis of AML, and presence of chromosome 5 and/or 7 abnormalities. Most importantly, the patients who were studied and
those who were not had similar outcomes.
To show the presence of VEGF, we used Western blot. Quantification of
VEGF was performed with solid-phase radioimmunoassay (RIA). We describe
these methods below.
Protein extraction.
Protein extraction was performed as previously described.25
Cell pellets were lysed for 30 minutes on ice in TENN buffer (50 mmol/L
Tris-HCL [pH 7.4], 5 mmol/L EDTA, 0.5% Nonidet P-40, and 150 mmol/L
NaCl supplemented with 1 mmol/L phenylmethylsulfonyl fluoride, 2 µg/mL leupeptin, and 2 µg/mL pepstatin). Frequent vortexing was
performed, and samples were then left on ice for 1 hour. Lysates were
clarified by microcentrifugation for 1 hour at 14,000 rpm. Protein
concentration was determined by the Bradford method, and 200 µg of
cell extract was run on a 9.5% sodium dodecyl sulfate-polyacrylamide
gel electrophoresis (SDS-PAGE), and stained with coomassie blue R-250
to check the protein profile and amount of protein loaded.
Western blot analysis of VEGF protein.
Two hundred micrograms of cell extract from AML patients and from
normal individuals was electrophoretically separated on 12.5% SDS-PAGE
gels and were transferred to nitrocellulose membrane papers. The
nitrocellulose membranes were blocked for 6 to 8 hours at room
temperature with 5% nonfat milk in phosphate-buffered saline (PBS)
containing 0.1% Tween 20 and 0.01% sodium azide. The blots were then
incubated over night at 4°C with goat anti-VEGF polyclonal antibody
(R&D Systems, Minneapolis, MN), at a concentration of 1 µg/mL in PBS containing 2.5% nonfat milk, 2.5% bovine serum albumin
(BSA), and 0.1% Tween 20. The membranes were washed with PBS
containing 0.1% Tween 20. The blots then were incubated with 1:2,000
diluted antigoat immunoglobulin linked to horseradish peroxidase
(Sigma, St Louis, MO) in PBS containing 1% nonfat milk and 0.1% Tween 20. Immunoreactive bands were developed using the ECL
detection system (Amersham, Arlington Heights, IL). After ECL detection, the membranes were stripped off from primary and secondary antibodies under conditions recommended by Amersham Inc, and
the stripped membranes were then blocked and probed with antiactin
monoclonal antibody IgM (Amersham) to check for equal loading of
protein in each lane. The Western blot bands were scanned and intensity
analyzed using Scan Analysis software from Biosoft (Cambridge, UK).
There was no visible band in samples with VEGF less than 2 as
determined by RIA (see below). However, considering cases with visible
bands, we found good correlation between Western blot and RIA with R = 0.72.
Solid-phase RIA.
VEGF protein levels were measured using solid-phase RIA as previously
detailed.25 Microtiter plates were coated overnight at
4°C with 5 µg of protein extracted from AML patients and normal individuals in 50 µL of PBS. The RIA plates were then washed with PBS
and blocked with 100 µL of 1% BSA (Amersham) in PBS for 1 hour at
37°C. The plates were incubated overnight at 4°C with 50 µL
of rabbit anti-VEGF antibody (Santa Cruz Biotech, Santa Cruz, CA)
diluted 1:1,000 in PBS containing 1% BSA. The plates were then washed
with PBS and amplified with goat anti-rabbit IgG antisera (Sigma)
diluted 1:1,000 in 0.1% BSA in PBS for 2 hours at 37°C. After
washing, the plates were developed for 2 hours at room temperature with
excess 125I-labeled protein G in 0.1% BSA in PBS per well.
The specific activity in each well varied between 150,000 to 200,000 cpm dependent on the activity of the 125I. They were then
washed with PBS, separated into individual wells, and the counts in
each well were recorded with a gamma counter (LKB Biotechnology,
Uppsala, Sweden). The assays were performed in triplicate, and the
results were corrected for the nonspecific binding (1% to 2%)
detected in control wells, which were not coated with a test antigen,
but were blocked with BSA. A second set of plates was incubated with
antiactin antibodies to confirm the use of equal amount of total
cellular protein from each sample. Each sample was tested in triplicate
and repeated twice in 2 different experiments. No significant
difference was observed between measurements. Normal samples were
repeated with each experiment and each plate contained 2 or more normal
samples. The linear range of the RIA was determined by using mixing
studies and purified VEGF from a commercially available kit (R&D
System). The levels of VEGF detected using cell lysates (5 µg of
total cell lysate) is extremely low and below the linear range of the
commercially available ELISA assay. However, using diluted purified
VEGF obtained from R&D, we established the linear range for our RIA as
between 0.5 and 62 pg. All analyzed samples were in the linear range (1 to 10 pg). The median cpm detected in 31 normal bone marrow samples was
assigned a score of 1 and the levels of the VEGF in AML samples were
normalized to the median of the normal bone marrow. However, some VEGF
protein expression was detected in normal individuals by solid phase
RIA. The range of the VEGF in normal bone marrow samples was between
0.84 and 1.16.
Statistical methods.
Associations between patient characteristics (covariates) were assessed
for pairs of numerical variables by Spearman correlation, for
categorical and continuous variables by Wilcoxon-Mann-Whitney and
Kruskal-Wallis test statistics, and for pairs of categorical variables
by the Fisher exact test and its generalizations. Patients with acute
progranulocytic leukemia (APL) were excluded from analysis of the
effect of VEGF on treatment outcome. The outcomes studied were
achievement of complete response (CR), survival, and disease-free survival from start of treatment and from CR date (events = relapse, death in CR). We examined the following covariates as assessed before
treatment as potential predictors of outcome: age, WBC count, platelet
count, performance status (Zubrod 0 to 2 v 3 to 4), treatment
in the protected environment (PE), cytogenetics (normal karyotype,
including patients with insufficient metaphases analysis v
inv[16] or t[8;21] v 5, 5q, 7 or
7q [5/7] v other abnormalities),
presence of an AHD, VEGF level, and whether the source of VEGF was
marrow or peripheral blood blasts. We also examined the effect of
treatment (Idarubicin + Ara-C v Idarubicin + Ara-C + Fludarabine). Logistic regression was used to assess the ability of the
patients' characteristics to predict the probability of CR, with
goodness-of-fit assessed by residual and partial residual scatter plots
and likelihood ratio (LR) statistics. Unadjusted time-to-event analyses
were performed using Kaplan-Meier plots. The Cox proportional hazards
model26 and its generalizations27 were used to
assess the ability of treatment groups and patient characteristics to
predict survival, with goodness-of-fit assessed by the
Grambsch-Therneau test,27 Schoenfeld residual plots, martingale residual plots,28 and LR statistics. All
scatterplots were smoothed using the lowess methods of
Cleveland,29 with variables transformed as appropriate
based on these plots. Multivariate logistic and Cox models
were obtained by performing a backward elimination with P value
cut-off .05, then allowing any variable previously deleted to enter the
final model if its P value was <.05. All computations were
performed on a DEC Alpha 2100 5/250 system computer (Digital
Electronics Corp, Nashua, NH) in StatXact (Cytel Software Corp,
Cambridge, MA) and S plus, using both standard S plus functions and the
survival analysis package of Therneau (gift of Dr T.M. Therneau, Mayo
Clinic, Rochester, MN).
| |
RESULTS |
The amount of VEGF detected using Western blot was in good agreement
with the amount detected using RIA (Fig 1).
The RIA values of AML samples were normalized to the RIA values of
normal bone marrow, which were assigned a value of 1. There was
considerable variability in the patients' RIA values (median, 2.8;
mean, 2.9; average, 0.5 to 8.1). While we did not asses the effect of
length of storage on VEGF levels by comparing the levels in a given
sample as measured in 1996 and as measured again in 1997 or 1998, those VEGF samples obtained in 1996 had similar values as those obtained in
1997 and 1998. However, VEGF levels as measured in blood were higher
than those measures in marrow (mean, 3.1 v 2.8; median, 3.6 v 2.9), although the difference was only marginally significant (P = .08). There was a strong correlation between VEGF as
quantified by RIA in blood and quantified in marrow in 9 patients in
whom we have both samples available (P = < .01).
View larger version (29K):
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| Fig 1.
Western blot. In lane C is a positive control, the next 2 lanes show control from 2 normal bone marrows. Lanes 1 through 13 show
a considerable variability in expression of VEGF that was confirmed
with RIA.
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There was no relationship between VEGF concentration and such standard
prognostic factors as age (P = .57), performance status (P = .12), karyotype (P = .40)
(Table 2), or presence of antecedent hematologic disease probably signifying a prior myelodysplastic syndrome. There was also no correlation between VEGF concentration and
pretreatment blood count. After excluding the 9 of our 99 patients who
had APL, we compared CR rate and survival according to whether VEGF was
above or below the median value (2.9). The CR rate was 64% in both
groups and survival was also the same in both. However, it was possible
that the relationship between VEGF and outcome was more complicated,
and to examine the specific nature of this relationship, we used
Martingale residual plots. These suggested that as VEGF continued to
increase to a value of about 1.7, CR rate continued to decrease, and
survival continued to shorten. At VEGF levels >1.7, there was no
further effect. Hence, we compared CR rates and survival in patients
who had VEGF levels above and below 1.7. Table 2 illustrates that CR
rates were 59% and 84% in patients with VEGF levels above and below this value, respectively. The difference in CR rates was a result of a
higher incidence of "resistance," ie, failure to achieve CR
despite living at least 35 days from the start of induction therapy.
The lack of an association between VEGF levels and conventional
prognostic factors noted above suggested that VEGF was an independent
predictor factor at least for CR. We tested this suggestion by fitting
a logistic model for CR and Cox model for survival and disease-free
survival from start of therapy and from CR date (Table 3). In these models, we examined
VEGF as a continuos variable as suggested by the Martingale residual
plots. Table 3 shows that VEGF was a predictor of each outcome even
after accounting for the other predictors. Of note, the source of the
cells used to measure VEGF (marrow v peripheral blood) was not
a predictor of outcome, or was the year when the sample was obtained.
This suggests that results were not biased by the length of sample storage, eg, systematically lower levels in samples obtained in 1996 than in samples obtained in 1998. Within the limits of small numbers,
there was no interaction between VEGF and cytogenetic groups, ie, the
effect of VEGF on outcome was not greater in any cytogenetic group.
Treatment with fludarabine-containing regimens was associated with poor
outcome as previously noted,30,31 but the effect of VEGF on
outcome remained after accounting for treatment.
| |
DISCUSSION |
Our data suggest that VEGF levels are, on average, higher in AML than
in normal bone marrow. Normal marrow contains relatively few blasts,
and high expression in a small number of normal blasts could easily
have been missed. However, Fiedler et al24 have reported
that normal CD34+ marrow cells have low VEGF levels. The
principal purpose of this report was to examine the possible prognostic
significance of cellular VEGF in AML. Our results suggest that cellular
VEGF levels are prognostic in newly-diagnosed AML (Tables 3) (APL
patients excluded from the analysis). Although we did not study
consecutive patients, the population we analyzed was representative of
our newly-diagnosed AML population (Table 1) with the principal
exception of higher white blood cell and blast counts and a slightly
higher incidence of inv(16). The higher white blood cell counts reflect the selective use of samples containing a high number of blasts so as
to facilitate VEGF measurements. Because of the selected nature of our
population, our conclusions about the prognostic significance of VEGF
cannot be generalized to the usual AML population, which of course has
a lower white blood cell count (Table 1). Three other possibly
confounding factors are the various treatments the patients received
(Table 1), the possible effect of storage on VEGF levels, and the
source of the cells used to measure VEGF. However, multivariate
analysis found that VEGF was still prognostic after accounting for the
unfavorable effect of fludarabine, and found that outcome was
unaffected by the year (1996, 1997, 1998) the sample was obtained or
whether the cells were obtained from blood or bone marrow.
The mechanism by which high cellular VEGF levels affect prognosis is
not clear. We are currently attempting to correlate VEGF levels with
marrow microvascular density and with plasma VEGF levels. Such levels
were unavailable in the 99 patients studied here. Regardless of the
mechanism, VEGF appears to be prognostic in at least the subset of
newly diagnosed AML patients presenting with relatively high WBC and
high blast count.
| |
FOOTNOTES |
Submitted January 18, 1999; accepted August 4, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Maher Albitar, MD, Section of
Hematopathology, Division of Laboratory Medicine, The University of
Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 72, Houston,
TX 77030-4095; e-mail: malbitar{at}mdacc.tmc.edu.
| |
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TOP
ABSTRACT
INTRODUCTION