The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1283-1287
Copyright © 1999 by The Endocrine Society
Insulin-Like Growth Factor Binding Proteins (IGFBPs) and IGFBP-Related Protein 1-Levels in Cerebrospinal Fluid of Children with Acute Lymphoblastic Leukemia1
Huey Kiam How,
Allen Yeoh,
Thuan Chong Quah,
Youngman Oh,
Ron G. Rosenfeld and
Kok-Onn Lee
Department of Medicine (H.K.H., K.-O.L.), Department of Pediatrics
(A.Y., T.C.Q.), National University of Singapore, Singapore 119074; and
Department of Pediatrics (Y.O., R.G.R.), Oregon Health Sciences
University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: K. O. Lee, Division of Endocrinology, Department of Medicine, 10 Kent Ridge Crescent, Singapore 119074. E-mail: mdcleeko{at}nus.edu.sg
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Abstract
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Abnormalities in insulin-like growth factor binding proteins
(IGFBPs) have been reported in the cerebrospinal fluid (CSF) of
children with acute leukemia. In the present study, we have further
characterized the IGFBPs in whole CSF prospectively in 11 children with
acute B-lineage lymphoblastic leukemia (ALL) undergoing chemotherapy.
Western ligand blots Western immunoblots using a new
anti-IGFBP-6 and a new IGFBP-rP1 (related protein-1 antibody and
immunoassays (Diagnostic Systems Laboratories, Inc.,
Webster, TX) were used to characterize and measure IGFBP-6, IGFBP-2,
IGFBP-3, and IGFBP-rP1 in children with ALL at diagnosis, and with
treatment. Comparisons at baseline were made with 11 children with
meningitis and 11 children with febrile convulsions (controls). The
mean (± SE) CSF IGFBP-6 in ALL patients, 56 (± 7) ng/mL,
was significantly lower than in meningitis, 97 (± 17) ng/mL; and in
controls, 123 (± 24) ng/mL (P < 0.05,
t test). In contrast, CSF IGFBP-3 was elevated in ALL
patients, 29 (± 9) ng/mL; compared with meningitis, 11 (± 1) ng/mL;
and controls, 10 (± 1) ng/mL (P < 0.05,
t test); and IGFBP-2 did not differ among the three
groups (47–59 ng/mL, P > 0.05). CSF IGFBP-6
remained very low in the patients with ALL, at 4 and 36 weeks of
treatment; whereas IGFBP-3 decreased to control levels, and IGFBP-2 did
not change significantly. At baseline, Western ligand blots and Western
immunoblots identified a 25- to 28-kDa broad band as IGFBP-6 and a
30-kDa band as IGFBP-2 and showed that there was almost no intact
IGFBP-3 in CSF. IGFBP-rP1 was also present in the CSF and was elevated
in patients with ALL, compared with the 2 control groups. In
conclusion, at diagnosis, IGFBP-rP1 and fragments of IGFBP-3 are
elevated, and IGFBP-6 is significantly decreased, in the CSF of ALL
children; and IGFBP-6 remained low, with treatment, up to 36 weeks. The
role of the IGFBPs and IGFBP-rPs in central nervous system acute
leukemia remain to be further elucidated.
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Introduction
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THE INSULIN-LIKE growth factor
(IGF)-binding proteins (IGFBPs) are a family of related proteins that
bind with high affinities to the IGFs. The IGFBPs are thought to
modulate the biological activities of the IGFs, but may also possess
biological activity independent of IGFs (1). Recent reports have
increasingly supported the hypothesis that IGFBPs may have direct,
receptor-mediated effects (2, 3). To date, at least 6 different IGFBPs
have been identified, with complete protein and complementary DNA
sequence, and a related protein (IGFBP-rP1, previously termed mac25 or
IGFBP-7) has been described (4, 5, 6). IGFBP-rP1 shares structural
homology with the IGFBPs in the N-terminal regions and binds IGFs with
low affinity.
Previous studies have shown that the major IGFBPs found in
cerebrospinal fluid (CSF) are IGFBP-2 and IGFBP-6, although IGFBP-3
fragments, IGFBP-4, and IGFBP-rP1 are also present (7, 8, 9). IGFBP-6,
first isolated in the CSF, along with IGFBP-2, has an increased
affinity for IGF-II, the major IGF in CSF (10). The predominance of
IGFBP-2 and IGFBP-6 in the CSF suggested that IGFBP-2 and IGFBP-6 have
some specific role in the central nervous system. IGFBP-6 has recently
been demonstrated to be elevated in the serum of children with chronic
renal failure (11) and in the CSF of patients with Alzheimer’s disease
(12), but it has not been described in other disease states.
We have reported previously that abnormalities in IGFBP levels in the
CSF might be important in childhood acute lymphoblastic leukemia (ALL)
(13, 14). Whereas IGFBP-3 levels in the CSF of childhood ALL were
significantly elevated, IGFBP-2 was normal (13, 14). In the present
study, we have used recently available immunoassays and specific
antibodies to further characterize IGFBP-rP1 and IGFBP-6 in
CSF and to measure prospectively the changes in CSF IGFBP-2, -3,
and -6 in childhood ALL patients. Our studies were performed in a
homogeneous group of B-lineage ALL patients with no malignant cells in
the CSF.
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Subjects and Methods
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Patients
CSF samples were obtained from 11 patients with B-lineage ALL
(mean age, 6 yr; 5 males and 6 females) and 11 patients with meningitis
(mean age, 10 yr; 5 males and 6 females). In addition, 11 children with
febrile convulsions, who were subsequently found to be normal, acted as
controls (mean age, 4 yr; 5 males and 6 females). Samples of CSF were
obtained for diagnostic purposes, and aliquots of excess CSF were
stored immediately at -70 C. Routine diagnostic biochemistry and
microscopy of ultracentrifuged samples were performed for the CSF of
the ALL patients, and samples with microscopically quantified
erythrocyte counts over 20 erythrocytes/mL CSF or 5 leukocytes/mL CSF
were excluded from the study. No malignant cells were detected in the
CSF in ALL patients after cytocentrifugation.
Children with ALL were included in the study only when they were in a
clinically stable and not severely catabolic state. Samples of excess
CSF were also obtained from the children with ALL immediately before
intrathecal therapy, at 4 weeks and 36 weeks after initiating
treatment. Where there was quantitative limitation of the volume of
excess CSF available for study, priority was given for immunoassays
first, and subsequently for Western blots. There was sufficient CSF for
Western blotting for about half of each group of patients (5 or 6 of 11
in each group).
The study was carried out in compliance with the Declaration of
Helsinki and was approved by the Hospital Institutional Review
Board.
Western ligand blot (WLB) analysis
Proteins from CSF samples (150 µL) were size-fractionated by
SDS-PAGE and then electroblotted onto a nitrocellulose membrane
(0.2-µm pore size, Bio-Rad Laboratories, Inc., CA) using
a Semi-Phor unit (Hoefer Scientific, San Francisco, CA).
Membranes were dried, blocked with BSA (1% (wt/vol) in TBS
buffer). Membranes were then incubated overnight with 1.5 x
106 cpm [125I]IGF-1 or
[125I]IGF-II (Amersham, Aylesbury, UK), washed,
dried, and exposed to Hyper-film MP (Amersham). Band densities
were analyzed using AMBIS software (San Diego, CA).
Western immunoblot (WIB)
The CSF samples (150 µL) were subjected to nonreducing
electrophoresis and then electroblotted onto a nitrocellulose membrane
(0.2-mm pore size, Bio-Rad Laboratories, Inc.) using a
Semi-Phor unit (Hoefer Scientific, CA). Membranes were dried and were
blocked with BSA (1% (wt/vol) in TBS buffer). The membrane was
then incubated overnight at 4 C with the different first antibodies
(anti-IGFBP-1, 
-Hec-1a, anti-IGFBP-6, and anti-IGFBP-rP1) and washed
three times for 15 min in Tween-20 (0.1%, vol/vol). After incubation
with goat antirabbit IgG conjugated with horseradish peroxidase, the
membrane was then washed in Tween-20 buffer (3 times for 15 min). The
membrane was then exposed to the ECL reagents (Amersham) for 1 min,
placed in Saran-Wrap, and exposed to x-ray film.
Antibodies
The Hec-1a, an antibody against human IGFBP-2 and human
IGFBP-3, and anti-IGFBP-rP1 antibodies have been described
previously (9, 13). The BP-6/95 that recognizes IGFBP-6 was
generously provided by Professor R. C. Baxter (Sydney, Australia).
The concentrations of the antibodies used were 1:40,000; 1:5,000; and
1:8,000, respectively. Anti-IGFBP-1 antibodies were purchased from
Diagnostic Systems Laboratories, Inc. and were used at a
concentration of 1:40,000.
IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-6 RIA
IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-6 levels in CSF were
measured by immunoassays (Diagnostic Systems Laboratories, Inc.) in batches. The CSF samples used for the IGFBP-2 and
IGFBP-6 immunoassays were diluted 1:3 with the diluent provided. There
was no dilution for IGFBP-1 and IGFBP-3 immunoassays. Intraassay
coefficients of variation for all the assays were less than 10%.
Statistics
Values are expressed as mean and SE. Statistical
comparison was performed using SAS Software (SAS Institute, Inc., Cary, NC).
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Results
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Samples of CSF from 11 patients with ALL were obtained and
compared with the CSF from 11 patients with meningitis and 11 control
patients with febrile convulsions. Table 1
shows the levels of IGFBP-2, IGFBP-3,
and IGFBP-6 in the CSF of all three groups, measured by RIA or
immunoradiometric assay. IGFBP-1 was undetectable in the CSF samples of
all three groups (data not shown). The mean IGFBP-3 concentration in
the CSF of ALL patients was significantly elevated, compared with the
mean IGFBP-3 concentration in control (P < 0.05) and
meningitis patients (P < 0.05). In contrast, the mean
IGFBP-6 concentration in ALL patients was significantly lower, compared
with control (P < 0.05) and meningitis patients
(P < 0.05) (see Fig. 1).
The differences in the mean IGFBP-2 levels between patients with ALL at
diagnosis, and the control and meningitis patients, were not
statistically significant.
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Table 1. Mean (± SE) levels of IGFBP-2, IGFBP-3, and IGFBP-6
(measured by RIA and immunoradiometric assay) in CSF of patients with
acute leukemia, meningitis, and controls
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Figure 1. IGFBP-6 concentrations in CSF (see Table 1 )
in ALL (n = 11), meningitis (n = 11), and controls admitted
with febrile convulsions (n = 11).
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Figure 2 shows a representative
[125I]IGF-I WLB of CSF from three patients with
meningitis (lanes 1–3), three patients with ALL (lanes 4–6), three
control samples (lanes 7–9), and a serum sample (S, lane 10). There
was one main band with a molecular mass of approximately 30 kDa
seen in all three groups. This corresponds to the known molecular mass
of IGFBP-2 shown in previous studies in CSF (14).
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Figure 2. A representative [125I]IGF-I
WLB of CSF from children with meningitis (lanes 1–3), ALL (lanes
4–6), controls (lanes 7–9), and normal serum (lane 10). After
SDS-PAGE (10% gel), the IGFBPs were transferred onto nitrocellulose,
incubated with [125I]IGF-I, and identified by
autoradiography.
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Figure 3 shows a WLB using
[125I]IGF-II only as the ligand. This second WLB clearly
shows the preferential affinity of the IGFBPs in CSF for IGF-II. The
30-kDa band seen in the earlier WLB (Fig. 1, using
[125I]IGF-I) was again clearly seen. In addition, a
larger predominant band, which bound [125I]IGF-II at
25–28 kDa, was demonstrated. These two bands were present in the CSF
of all the patients studied.
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Figure 3. A representative [125I]IGF-II
WLB of CSF from children with meningitis (lanes 1–3), ALL (lanes
4–6), controls (lanes 7–9), and normal serum (lane 10). After
SDS-PAGE (10% gel), the IGFBPs were transferred onto nitrocellulose,
incubated with [125I]IGF-II, and identified by
autoradiography.
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Figure 4 shows a WIB using a specific
IGFBP-6 antibody (gift of Professor R. C. Baxter, BP6/95) at
1:8000 concentration, of the same CSF samples as in Figs. 2 and 3. This
WIB clearly identifies the major [125I]IGF-II binding
band shown in Fig. 2 to be IGFBP-6. A similar WIB, using the Hec-1a
antibody (which specifically binds IGFBP-2 and IGFBP-3), confirmed the
band at 30 kDa to be IGFBP-2 and confirmed that lower molecular mass
fragments of IGFBP-3 were present (data not shown).
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Figure 4. WIB analysis of CSF IGFBPs. The antibodies
used were BP-6/95, at a concentration of 1:8000. Samples were
electrophoresed, transferred, and incubated with the antibodies. The
binding was detected after incubation with goat antirabbit
IgG-conjugated horseradish peroxidase and fluorescent substrates.
Meningitis, lanes 1–3; ALL, lanes 4–6; controls, lanes 7–9; normal
serum, lane 10.
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Figure 5 shows a WIB using an antibody
that recognizes the recently described human IGFBP-rP1 (5). This WIB
revealed a band at approximately 27–29 kDa, which did not correspond
to any of the bands that bound to [125I]IGF-I or
[125I]IGF-II (Figs. 2 and 3). The patients with ALL
(lanes 4–6) showed much more binding to antibody, compared with the
patients with meningitis (lanes 1–3) or febrile convulsions (lanes
7–9). The qualitative data from this and other WIBs indicated that
IGFBP-rP1 was present in greater abundance in the CSF from ALL
children, compared with the other two groups.
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Figure 5. WIB analysis of CSF IGFBPs. The antibodies
used were anti-IGFBP-rP1, at a concentration of 1:10,000. Samples were
electrophoresed, transferred, and incubated with the antibodies. The
binding was detected after incubation with goat antirabbit
IgG-conjugated horseradish peroxidase and fluorescent substrates.
Meningitis, lanes 1–3; ALL, lanes 4–6; controls, lanes 7–9; normal
serum, lane 10.
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An immunoblot with anti-IGFBP-1 antibodies did not yield a band in any
of the three groups (data not shown).
Longitudinal analysis of IGFBPs in CSF
Figure 6 shows the mean levels (with
SE bars) of IGFBP-2, IGFBP-3, and IGFBP-6 in the
CSF (measured by immunoassay) in children with ALL. Samples were
obtained from excess CSF available from routine diagnostic procedures
in the patients with ALL before the initiation of therapy and at 4
weeks and 36 weeks, when intrathecal chemotherapy was given. The mean
level of CSF IGFBP-3, which was elevated at diagnosis, compared with
the two control groups, decreased at week 4 and decreased further to
the levels of the other two control groups by week 36. In contrast, the
mean levels of IGFBP-6, which were significantly lower than those of
the two other control groups, continued to decrease further at weeks 4
and 36. This further decline in the already-low IGFBP-6 levels was
surprising and was statistically significant. In contrast, the small
changes in the mean levels of IGFBP-2 were not statistically
significant.
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Figure 6. Longitudinal measurements of IGFBP-2,
IGFBP-3, and IGFBP-6 in the CSF of 11 ALL patients. The CSF samples
were taken before the start of therapy, 4 weeks after therapy, and 36
weeks after therapy. Values are means of 11 patients
(bars, SE; *, P <
0.05).
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Discussion
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In the present study, we have measured and compared the IGFBPs in
CSF in 11 children with B-lineage ALL with CSF IGFBP concentrations in
2 other groups of children, 11 children with meningitis, and 11
children with febrile convulsions subsequently shown to be normal. Our
data shows ALL patients to have normal IGFBP-2 levels, elevated IGFBP-3
levels, lower IGFBP-6 levels, and increased IGFBP-rP1 in the CSF.
Our finding that ALL patients without central nervous system
involvement had normal CSF IGFBP-2 level confirms an earlier
observation (14), and it provides evidence that the differences in the
other IGFBP concentrations are not artefactual or a result of serum
contamination of the CSF. The IGFBP-2 concentrations in CSF of ALL
children in our study (59 ng/mL) is comparable with the previously
published value of 51 ng/mL (14). However, the WLB data in Figs. 2 and 3 suggests that IGFBP-2 in ALL may be lower than that in controls,
which may possibly represent proteolysis of IGFBP-2 in the CSF of
ALL patients.
The present study also found significantly elevated IGFBP-3
concentrations in the CSF of ALL patients and demonstrated that the
elevated IGFBP-3 decreased with time, to levels similar to that of the
control patients. This is the first description of longitudinal changes
in any of the IGFBPs with time, and it supports our earlier suggestion
that the IGFBPs may be directly relevant in the pathophysiology of
childhood acute leukemia (13). The recent evidence that IGFBP-3 and
IGFBP-3 fragments may have independent biological action (3, 15, 16)
further supports the possibility of a role of IGFBP-3 in childhood ALL,
because the significant elevations in CSF IGFBP-3 concentrations in our
patients were specific to the ALL group and declined significantly with
effective treatment of the ALL. The concentrations of IGFBP-3 in the
CSF of our ALL patients were lower than the IGFBP-3 values reported
earlier (13), and it is possible that the standards or sensitivities of
the different immunoassays might account for this difference. Another
possible factor is the heterogeneity of the acute leukemia patients in
that earlier study, whereas all the ALL patients in our present study
had leukemia of B-lineage.
We also report, for the first time, quantitative data using a newly
available RIA on IGFBP-6 levels in the CSF of children, and qualitative
confirmation for the high affinity for IGF-II of IGFBP-6 on WLB. The
levels of CSF IGFBP-6 were significantly lower in the children with
ALL, compared with those in patients with meningitis and with the
controls with febrile seizures (56 ng/mL vs. 97 and 123
ng/mL, respectively). This decrease was surprising and cannot be
attributed to a lower CSF protein concentration, because the same
samples were used to measure IGFBP-2 and IGFBP-3. Data about IGFBP-6
levels in the CSF are limited. Baxter and Saunders (17) reported that
normal adult CSF contained about 152 ng/mL IGFBP-6. Tham et
al. (12) also reported an increase of IGFBP-2 and IGFBP-6 in the
CSF of patients with Alzheimer’s dementia. To our knowledge, there is
no other quantitative data about IGFBP-6 in CSF, and certainly no
longitudinal data on changes in CSF IGFBP-6 levels. The decrease in
IGFBP-6 levels in the CSF of ALL patients could be physiologically
significant, because the selective affinity of IGFBP-6 for IGF-II is 70
times stronger than its affinity for IGF-I, and the concentration of
IGF-II is over 30 times that of IGF-I in the CSF of ALL patients
(10, 13, 18). Thus, a decrease in CSF IGFBP-6 level might alter the
IGF-II/IGFBP ratio in the CSF. Our finding of significantly lower CSF
IGFBP-6 concentrations in CSF of ALL patients, which then decreased
even further with time, suggests that IGFBP-6 levels might be related
nonspecifically to inflammation found in meningitis and febrile
convulsions, rather than to the leukemic process. The continued
decrease with time, in the patients with ALL, to even lower levels
suggest that normal CSF IGFBP-6 in children is much lower. The
significantly higher levels shown in the children with meningitis and
febrile convulsions may, thus, represent nonspecific neuronal damage
and may be the same reason for the increase in CSF IGFBP-6 reported in
patients with Alzheimer’s disease (12).
Our suggestion is limited, as in all clinical studies, by the
unavailability of CSF from completely healthy and true normal children.
It is still possible that normal CSF IGFBP-6 concentrations are higher,
and therefore closer to the values in our control and meningitis
groups. We would then have to postulate that the low CSF IGFBP-6
concentrations in the children with leukemia are specific to their
disease, which then become even lower with effective systemic
treatment. This, however, seems less likely a possibility, compared
with a normalization of CSF with treatment of the leukemia. However,
further confirmation of our suggestion of normal low CSF levels of
IGFBP-6 is difficult because of these constraints and may require
investigation with animal models.
Similarly, our hypotheses would also have been stronger if there had
been sufficient CSF for Western blotting and densitometric analysis in
every patient, and sufficient CSF for measurement of concentrations of
IGF-I and IGF-II peptides.
Recently, Wilson et al. (9) reported the presence of
IGFBP-rP1 in adult CSF. Our present study confirmed the presence of
IGFBP-rP1 in the CSF and showed its presence in all three groups of
children studied. Compared with levels in the two control groups, CSF
IGFBP-rP1 seems to be elevated in the acute leukemia patients. However,
because of the limitations of the present study resulting from the
current lack of a quantitative IGFBP-rP1 immunoassay, further studies
are needed to reassess the levels of IGFBP-rP1 in the CSF, to further
investigate these differences. The function of IGFBP-rP1 is not known
at the present time, but it has been hypothesized that IGFBP-rP1 has
direct growth-suppressing activity (19, 20). IGFBP-rP1 has been shown
to be relevant in the regulation of breast cancer cell lines (19) and
prostate cancer (20). Evidence has also been presented that IGFBP-rP1
binds to insulin with relatively high affinity (21); and thus, recently
we have proposed that IGFBP-rP1 and other low-affinity IGF binders be
categorized as IGFBP-rPs and that IGFBP-7 be termed: IGFBP-rP1 (6).
The description of the significant differences in IGFBPs in the present
study and the significant changes with time of IGFBP-3 and IGFBP-6 in
the CSF of these B-lineage ALL patients suggest that the alterations in
the CSF IGFBP-3, IGFBP-6, and IGFBP-rP1 could be important and specific
to childhood ALL. These alterations in IGFBPs and IGFBP-rP1 levels
could possibly be useful clinically as an early marker of disease
relapse or of sanctuary site involvement by ALL. Further studies will
be useful in determining and elucidating the role(s) of the IGFBPs and
IGFBP-rPs in childhood leukemia.
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Acknowledgments
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The authors are very grateful to Professor R. C. Baxter for
the generous gift of anti-IGFBP-6 antibodies.
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Footnotes
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1 This work was supported, in part, by research grants from the
National Medical Research Council Singapore 48/94 (to K.-O.L.
and T.C.Q.), Singapore Cancer Society (to K.-O.L. and T.C.Q.), NIH
Grants CA-58110 and DK-51513 (to R.G.R.), US Army Grants
DAMD-17–96-1–2604 and 17–97-1–7204 (to R.G.R.), and
Diagnostics Systems Laboratories, Inc. 
Received October 5, 1998.
Revised December 10, 1998.
Accepted December 28, 1998.
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Top
Abstract
Introduction
