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Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1508-1513
Expression of the Lung Resistance Protein Predicts Poor Outcome in De
Novo Acute Myeloid Leukemia
By
Martin Filipits,
Gudrun Pohl,
Thomas Stranzl,
Ralf W. Suchomel,
Rik J. Scheper,
Ulrich Jäger,
Klaus Geissler,
Klaus Lechner, and
Robert Pirker
From the Divisions of Oncology and Hematology, the Department of
Internal Medicine I, University of Vienna Medical School, Vienna,
Austria; and the Department of Pathology, Free University Hospital,
Amsterdam, The Netherlands.
 |
ABSTRACT |
The 110-kD lung resistance protein (LRP) is
overexpressed in P-glycoprotein-negative multidrug-resistant cell
lines and most likely involved in the multidrug resistance (MDR) of
these cell lines. To determine the clinical significance of LRP, we
have studied LRP expression of leukemic blasts and its association with
clinical outcome in patients with de novo acute myeloid leukemia (AML).
LRP expression of leukemic blasts obtained from peripheral blood or
bone marrow of previously untreated patients (n = 86) was
determined by immunocytochemistry by means of monoclonal antibody LRP-56. LRP expression at diagnosis was detected in 31 (36%) patients. LRP expression was independent of age and sex of the patients, French-American-British subtype, cytogenetic abnormalities, and lactate
dehydrogenase levels, but correlated with white blood cell count
(P = .01). Eighty-two patients received standard induction chemotherapy that included cytarabine and MDR drugs (daunorubicin in
most patients, additional etoposide in the majority of patients). The
complete remission rate of induction chemotherapy was 72% (95%
confidence interval [CI] = 61% to 82%) for the total study population. The complete remission rate was 81% (95% CI = 67% to
91%) for patients without LRP expression but only 55% (95% CI = 36% to 74%) for patients with LRP expression
(P = .01). Overall survival and disease-free survival were
estimated according to Kaplan-Meier in 82 and 59 patients,
respectively. Overall survival was significantly longer in patients
without LRP expression than in patients with LRP expression. At a
median follow-up of 16 months, median overall survival was 17 months
(95% CI = 12 to 38 months) for LRP-negative patients but only 8 months (95% CI = 4 to 12 months) for -positive patients
(P = .006). Disease-free survival was 9 months (95%
CI = 7 to 11 months) for LRP-negative patients and 6 months (95%
CI = 5 to 8 months) for -positive patients (P = .078). Outcome was best in patients lacking both LRP and P-glycoprotein expression. In conclusion, LRP predicts for poor outcome and thus the
LRP gene appears to be another clinically relevant drug
resistance gene in AML.
| |
INTRODUCTION |
ACUTE MYELOID leukemia (AML) lends itself
as a model disease for the evaluation of the clinically relevant
mechanisms of resistance toward anticancer drugs. Potential mechanisms
are those involved in the multidrug resistance (MDR)
phenotype.1,2 They include the MDR1 gene and the
recently characterized MRP (multidrug resistance protein)
gene.1,3 The MDR1 gene codes for P-glycoprotein (P-gp), which functions as an energy-dependent drug efflux pump for
natural hydrophobic compounds including anticancer drugs (eg, anthracyclines, epipodophyllotoxins).1 Like P-gp, MRP is a member of the ABC transporter family and mediates resistance to a
similar spectrum of anticancer drugs as P-gp.4 Both genes are involved in MDR of cell lines.1,3,4 Expression of
MDR1 RNA as well as P-gp have been shown to be associated with
worse outcome in AML.5-8 MRP is highly expressed in 26% of
AML samples but, in contrast to P-gp, this expression does not predict
for outcome of induction chemotherapy or survival of the
patients.9 Only in the subgroup of patients with inversion
in chromosome 16, patients with a deletion of the MRP gene had
a longer overall and disease-free survival.10 Whether
MRP gene deletion is the reason for the good prognosis of
patients with inversion in chromosome 16 remains unclear, because lack
of MDR1 RNA/P-gp expression might also explain the good
prognosis of patients with this AML subtype.11
Recently the lung resistance protein (LRP) was detected in MDR cell
lines and its gene has been cloned.12,13 The LRP
gene, located on chromosome 16 proximal to the MRP
gene,13,14 is homologous to the major vault protein of the
rat. Vaults are ribonucleoprotein particles that are located in the
cytoplasm and probably involved in transport
processes.15,16 LRP is thus believed to contribute to the
drug resistance of these cell lines, probably via affecting drug
transport. Consistent with this hypothesis, LRP overexpression was
associated with resistance to doxorubicin, vincristine, carboplatin, cisplatin, and melphalan.17 LRP is overexpressed in normal
colon tissue, normal lung tissue, renal proximal tubules, adrenal
cortex, and macrophages,18 but its physiological function
remains to be evaluated.
To determine whether LRP is a clinically relevant drug
resistance gene in de novo AML, we have studied LRP expression of AML cells and its relationship to clinical outcome in previously untreated patients with de novo AML. Here we report the results of this study.
| |
PATIENTS AND METHODS |
Patients.
Eighty-six patients (37 females, 49 males) with de novo AML who were
treated between January 1990 and February 1997 were studied after
obtaining informed consent. Sixty-five of these patients had been
included in a previous study on the clinical significance of
MRP.9 Eighty-two patients received standard induction
chemotherapy protocols, whereas 4 patients did not receive
chemotherapy. Treatment consisted of daunorubicin 45 mg/m2
daily on days 1-3 and cytarabine 200 mg/m2 daily on days
1-7 (DA protocol) in 21 patients and additional etoposide 100 mg/m2 daily on days 1-5 (DAE protocol) in 50 patients.
Three patients were treated with idarubicin plus cytarabine (IA
protocol). Six patients with French-American-British (FAB) subtype M3
received all-trans retinoic acid (ATRA) before chemotherapy.
Two patients received intermediate-dose cytarabine followed by the DAE
protocol as second induction chemotherapy cycle. Response to induction chemotherapy was assessed according to standard criteria.19 Four patients did receive only one treatment cycle which did not result
in complete remission (CR) and, therefore, these patients were
classified as not evaluable. Fifty-six out of 59 patients in complete
remission received consolidation therapy that included anthracylines
and/or cytarabine. Seventeen patients underwent bone marrow
transplantation.
Immunocytochemistry.
Mononuclear cells were isolated from either peripheral blood
(n = 37), bone marrow (n = 36) aspirates, or both sources
(n = 13) by Ficoll-Paque (Pharmacia, Uppsala, Sweden)
gradient centrifugation. Smears were prepared from fresh samples and
stored at  20°C until use. Cells were fixed in cold acetone
(20°C, 10 minutes), washed twice, and incubated in 3%
H2O2 to block endogenous peroxidase activity.
After two wash steps followed by a 20-minute incubation with normal
goat serum (Dako, Glostrup, Denmark; diluted 1:20), cells
were incubated for 2 hours with the monoclonal antibody (MoAb) LRP-56
(dilution 1:50) or MoAb C219 (Alexis, Läufelingen, Switzerland).
LRP-56 detects LRP. C219 recognizes P-gp but also cross-reacts with the
MDR2 gene product. Antibody binding was detected by the
avidin-biotin-peroxidase method. Bound peroxidase was developed with
3-amino-9-ethylcarbazole (Sigma Chemical Co, St Louis, MO)
and 0.1% H2O2 in acetate buffer pH 5.2. The
slides were counterstained with Mayer's Hämalaun and mounted
with Aquatex (Merck, Darmstadt, Germany). All washes were
performed in phosphate-buffered saline.
To ensure specificity of staining, several controls were performed.
Firstly, the small cell lung cancer cell line SW1573 and its
drug-resistant variant SW1573/2R120 were used as negative and positive
controls for LRP expression.12,13 Drug-sensitive KB-3-1 and
multidrug-resistant KB-8-5 cells (provided by Drs I. Pastan and M.M.
Gottesman, National Cancer Institute, Bethesda, MD) were used as
negative and positive controls for P-gp expression.5 Secondly, experiments without MoAbs were used as negative controls.
Karyotype analysis.
Cytogenetic analysis was performed as previously
described.20 Inversion in chromosome 16 (inv16), t(8;21),
or t(15;17) indicated good prognosis, and normal karyotype indicated
intermediate prognosis. Cytogenetic abnormalities others than the ones
described above were regarded as indicators of poor prognosis.
Survival analysis.
Overall survival and disease-free survival were estimated according to
Kaplan-Meier.21 Overall survival was measured from the time
of diagnosis until the time of either death or last control. Disease-free survival was measured from the time of complete remission until the time of relapse or death. Patients who underwent bone marrow
transplantation were censored at the time of transplantation.
Statistical analysis.
Frequencies were tested by chi-squared analysis or exact chi-squared
test. In addition, Kruskal-Wallis tests were performed. Comparisons of
survival curves were done with the log-rank test.
| |
RESULTS |
LRP expression in de novo AML at diagnosis.
Eighty-six AML patients were studied for LRP expression in their
leukemic cells at diagnosis. LRP expression was immunocytochemically determined by means of the MoAb LRP-56. Samples were scored LRP positive if  5% positive staining blasts were detected. LRP was positive in 31 of 86 (36%) patients (Table
1). LRP was positive in 20 of 50 (40%)
peripheral blood samples and 13 of 49 (27%) bone marrow samples. In
those 13 cases where samples from both sources were studied, no
differences between peripheral and bone marrow blasts were observed
(data not shown).
LRP and clinical parameters.
Next we studied the association of LRP with clinical parameters. The
major clinical and laboratory findings of the patients are summarized
in Table 1. The median age of the patients was 56 years (range, 15 to
88 years). LRP expression correlated with white blood cell count
(P = .01) but was independent of age, percentage of patients
older than 50 years, sex, serum lactate dehydrogenase levels, and
cytogenetic abnormalities (Table 1). Interestingly, 8 of 9 (89%)
patients with promyelocytic leukemia (FAB M3) did not express LRP, but
this was not significantly different from other FAB subtypes
(P = .1). Karyotype was categorized into three prognostic
groups (see Patients and Methods). LRP expression was not significantly
different between these groups (Table 1), although patients with good
prognosis karyotype showed a trend (P = .1) toward negative
LRP (Table 1).
LRP expression and outcome of induction chemotherapy.
Eighty-two patients received standard induction chemotherapy that
included cytarabine and MDR drugs. Four (5%) patients did not receive
chemotherapy. The treatment protocols were not different between
LRP-negative and LRP-positive patients (Table 1). The CR rate of
induction chemotherapy was 72% (95% confidence interval [CI] = 61% to 82%) for the total study population. Resistant
disease (after at least two treatment cycles) and early death (within 4 weeks after begin of treatment) occurred in 11% and 12% of the patients, respectively. Four (5%) patients were not evaluable for
response. The complete remission rate was 81% (95% CI = 67% to
91%) for patients without LRP expression but only 55% (95% CI = 36% to 74%) for patients with LRP expression
(P = .01) (Table 2). Resistant
disease was seen in 4 (8%) (95% CI = 2% to 18%) LRP-negative and
in 5 (17%) (95% CI = 6% to 36%) LRP-positive patients. Early
death occurred in 5 (9%) (95% CI = 3% to 21%) negative and 5 (17%) (95% CI = 6% to 36%) positive patients (Table 2). When only
patients who received induction chemotherapy with daunorubicin/cytarabine (DA) or daunorubicin/cytarabine/etoposide (DAE)
(n = 77) were analyzed, similar results were obtained as CR rate was
80% for LRP-negative patients and 58% for LRP-positive patients
(P = .03) (data not shown).
LRP and survival.
Overall survival and disease-free survival were estimated according to
Kaplan-Meier in 82 and 59 patients, respectively. Relapses and deaths
occurred in 41 and 54 patients, respectively. Both overall survival and
disease-free survival were shorter in patients with LRP expression
(Figs 1 and 2).At a median follow-up of 16 months, median overall survival was 17 months (95% CI = 12 to 38 months) for LRP-negative patients but only
8 months (95% CI = 4 to 12 months) for LRP-positive patients
(P = .006). Nine of 10 patients surviving more than 2 years
did not express LRP in their leukemic blasts. Median disease-free
survival was 9 months (95% CI = 7 to 11 months) for LRP-negative and
6 months (95% CI = 5 to 8 months) for LRP-positive patients
(P = .078).
View larger version (12K):
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[in a new window]
| Fig 1.
LRP and overall survival. LRP expression of leukemic
cells was determined by immunocytochemistry and overall survival was estimated according to Kaplan-Meier in 82 patients. Survival data based
on LRP expression are shown.
|
|
View larger version (12K):
[in this window]
[in a new window]
| Fig 2.
LRP and disease-free survival. LRP expression of leukemic
cells was determined by immunocytochemistry and disease-free survival was estimated according to Kaplan-Meier in 59 patients. Disease-free survival based on LRP expression is shown.
|
|
LRP/P-gp status and clinical outcome.
Finally, we analyzed the combination of LRP and P-gp status in relation
to clinical outcome (Table 3). Consistent
with our previous studies on P-gp in AML,5,8,9 P-gp
expression was high, intermediate, and low in 12%, 30%, and 58% of
the patients, respectively (data not shown). High P-gp expression was
associated with lower CR rates (75% v 44%, P = .05)
and shorter survival (median overall survival: 13 months v 7 months, P = .03) (data not shown). No correlation was
observed between high P-gp expression and LRP expression (data not
shown). Response to induction chemotherapy was best (CR rate = 84%)
in patients lacking expression of both genes, intermediate (CR
rate = 57%) in those with expression of either of these two genes,
and worst (CR rate = 40%) in patients expressing both genes (Table
3). The CR rate was significantly higher in
LRP /P-gp patients as compared to the
remaining patients (P = .004). Overall survival and
disease-free survival were also significantly longer for patients with
LRP/P-gp leukemias as compared to the
remaining patients with a median overall survival of 24 versus 7 months
(P = .0002) and a median disease-free survival of 9 versus 6 months (P = .024) (data not shown).
| |
DISCUSSION |
In the present study we have shown the clinical significance of LRP in
AML on an unselected patient population. LRP expression of leukemic
cells was observed in 36% of AML patients at diagnosis and did predict
for both poor response to induction chemotherapy and shorter survival.
The percentage of LRP-positive AMLs is similar to the percentages
reported in two recent studies with a small sample
size.18,22 Izquierdo et al18 reported LRP
expression in 5 of 15 (25%) AML samples and List et al22
in 7 of 21 (33%) de novo AML samples.
The association of LRP expression with poor outcome stresses the
clinical relevance of LRP and also suggests that drug resistance in AML
is multifactorial, involving at least P-gp and LRP. This multifactorial
nature is further supported by the fact that prognosis is best in the
absence and worst in the presence of both proteins (Table 3). Results
similar to ours have recently been reported by List et
al,22 who found a trend of LRP expression toward worse
outcome on a heterogenous study population that included patients with
de novo, secondary, or relapsed AML.
Although an association of LRP expression with high white blood cell
counts was seen (Table 1), the poor outcome of LRP-positive patients
cannot be explained by their higher white blood cell count because in
our study white blood cell count (cut-off levels of 20,000 or
100,000) had no impact on outcome of induction
chemotherapy or survival (data not shown). Lack of LRP expression was
seen in most FAB M3 patients (Table 1) and this might contribute to the
good response to anthracyclines as well as good prognosis of this AML
subtype.23 Because LRP expression showed a trend toward CD7
expression,22 future studies will have to further address
the association of LRP with surface markers. Future studies on large
patient populations are also required to determine whether the impact
of LRP expression on clinical outcome depends on the type of induction
or consolidation chemotherapy.
LRP expression was also observed in several solid
tumors.18,24 LRP predicted for both response to
chemotherapy and prognosis in advanced ovarian carcinoma,24
but the clinical relevance of LRP in other solid tumors remains to be
determined. The mechanisms by which LRP exerts drug resistance will
have to be elucidated in future studies.
In conclusion, the LRP gene appears to be another clinically
relevant drug-resistance gene in AML and probably other malignancies. This will have to be taken into consideration in the planning of
strategies to overcome drug resistance in cancer patients and warrants
the pharmaceutical development of resistance modifiers not only of P-gp
function25,26 but also of LRP function.
| |
FOOTNOTES |
Submitted August 22, 1997;
accepted December 2, 1997.
Supported by the `Fonds zur Förderung der wissenschaftlichen
Forschung' (Project No. P12264-MED).
Address reprint requests to Robert Pirker, MD, Associate Professor,
Division of Oncology, Department of Internal Medicine I, University of
Vienna Medical School, Währinger Gürtel 18-20, A-1090
Vienna, Austria.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be here-by marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract