Download Expression of the Lung Resistance Protein Predicts

From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
RAPID COMMUNICATION
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
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 5 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 5 .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] 5 61% to 82%) for the total
study population. The complete remission rate was 81%
(95% CI 5 67% to 91%) for patients without LRP expression
but only 55% (95% CI 5 36% to 74%) for patients with LRP
expression (P 5 .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 5 12 to 38
months) for LRP-negative patients but only 8 months (95%
CI 5 4 to 12 months) for -positive patients (P 5 .006). Diseasefree survival was 9 months (95% CI 5 7 to 11 months) for
LRP-negative patients and 6 months (95% CI 5 5 to 8 months)
for -positive patients (P 5 .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.
r 1998 by The American Society of Hematology.
A
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.
CUTE 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
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.
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.
r 1998 by The American Society of Hematology.
0006-4971/98/9105-0039$3.00/0
1508
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
Blood, Vol 91, No 5 (March 1), 1998: pp 1508-1513
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
LRP IN AML
1509
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 5 37), bone marrow (n 5 36) aspirates, or both
sources (n 5 13) by Ficoll-Paque (Pharmacia, Uppsala, Sweden) gradient centrifugation. Smears were prepared from fresh samples and stored
at 220°C until use. Cells were fixed in cold acetone (220°C, 10
minutes), washed twice, and incubated in 3% H2O2 to block endog-
Table 1. Characteristics of Patients
LRP2 Patients
n (%)
LRP1 Patients
n (%)
86
55 (100)
31 (100)
56
15-88
52
54
15-88
31 (56)
61
18-82
21 (68)
49
37
33 (60)
22 (40)
16 (52)
15 (48)
14,380
400-250,000
52,300
740-280,700
All Patients
No. of patients
Age (yr)
Median
Range
Patients .50 yr
Sex
Males
Females
White blood cell count
Median
Range
FAB subtype
M0
M1
M2
M3
M4
M4Eo
M5
M6
Lactate dehydrogenase (U/L)
Median
Range
Karyotype (n 5 79)§
Good prognosis\
Intermediate prognosis
Poor prognosis
Induction therapy§
DA
DAE
IA
ATRA 1 DA or DAE
Intermed.-dose cytarabine 1 DAE
None
Consolidation therapy
DA
DAE
Intermed.-dose cytarabine
High-dose cytarabine
C-HAM
DAE 1 intermed.-dose cytarabine
DAE 1 high-dose cytarabine
None
Bone marrow transplantation
21,750
400-280,700
5
16
22
9
16
5
10
3
463
104-3,800
2 (4)
9 (17)
17 (31)
8 (15)
9 (16)
3 (5)
4 (7)
3 (5)
3 (10)
7 (23)
5 (16)
1 (3)
7 (23)
2 (6)
6 (19)
0 (0)
P
0.1*
0.3†
0.5†
0.01*
0.2‡
433
104-2,460
583
194-3,800
0.1*
20
29
30
16 (29)
19 (35)
17 (31)
4 (13)
10 (32)
13 (42)
0.3‡
21
50
3
6
2
4
14 (25)
31 (56)
1 (2)
6 (11)
1 (2)
2 (4)
7 (23)
19 (62)
2 (6)
0 (0)
1 (3)
2 (6)
17
25
4
6
1
2
1
3
17
14 (33)
16 (37)
3 (7)
4 (9)
1 (2)
2 (5)
1 (2)
2 (5)
13 (24)
3 (19)
9 (56)
1 (6)
2 (13)
0 (0)
0 (0)
0 (0)
1 (6)
4 (13)
*Kruskal-Wallis test.
†Chi-square test.
‡Exact chi-squared test.
§Protocols and karyotype classification are described in Patients and Methods.
\Good prognosis versus all other karyotypes: P 5 .1.
0.4‡
0.9‡
0.2†
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
1510
FILIPITS ET AL
Table 2. LRP and Outcome of Induction Chemotherapy
Total
LRP2 patients
LRP1 patients
No. of
Patients
Complete
Remission
Resistant
Disease
Early
Death
Not
Evaluable
82
53
29
59 (72%)
43 (81%)
16 (55%)
9 (11%)
4 (8%)
5 (17%)
10 (12%)
5 (9%)
5 (17%)
4 (5%)
1 (2%)
3 (11%)
LRP expression of leukemic cells was compared with outcome of
induction chemotherapy. Induction chemotherapy protocols are described in Patients and Methods. Statistical analysis (chi-squared test)
for complete remission: P 5 .01.
enous peroxidase activity. After two wash steps followed by a 20minute 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 drugresistant variant SW1573/2R120 were used as negative and positive
controls for LRP expression.12,13 Drug-sensitive KB-3-1 and multidrugresistant 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 remis-
sion 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 5 .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 5 .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 5 .1) toward negative LRP (Table 1).
LRP expression and outcome of induction chemotherapy.
Eighty-two patients received standard induction chemotherapy
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.
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
LRP IN AML
1511
Fig 2. LRP and disease-free
survival. LRP expression of leukemic cells was determined by immunocytochemistry and diseasefree survival was estimated
according to Kaplan-Meier in 59
patients. Disease-free survival
based on LRP expression is
shown.
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] 5 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 5 67% to 91%) for patients
without LRP expression but only 55% (95% CI 5 36% to 74%)
for patients with LRP expression (P 5 .01) (Table 2). Resistant
disease was seen in 4 (8%) (95% CI 5 2% to 18%) LRPnegative and in 5 (17%) (95% CI 5 6% to 36%) LRP-positive
patients. Early death occurred in 5 (9%) (95% CI 5 3% to 21%)
negative and 5 (17%) (95% CI 5 6% to 36%) positive patients
(Table 2). When only patients who received induction chemotherapy with daunorubicin/cytarabine (DA) or daunorubicin/
cytarabine/etoposide (DAE) (n 5 77) were analyzed, similar
results were obtained as CR rate was 80% for LRP-negative
patients and 58% for LRP-positive patients (P 5 .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 5 12 to 38 months) for
LRP-negative patients but only 8 months (95% CI 5 4 to 12
months) for LRP-positive patients (P 5 .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 5 7 to 11 months) for LRP-negative and 6
months (95% CI 5 5 to 8 months) for LRP-positive patients
(P 5 .078).
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 5 .05) and shorter survival
(median overall survival: 13 months v 7 months, P 5 .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 5 84%) in patients
lacking expression of both genes, intermediate (CR rate 5 57%)
in those with expression of either of these two genes, and worst
(CR rate 5 40%) in patients expressing both genes (Table 3).
The CR rate was significantly higher in LRP2/P-gp2 patients as
compared to the remaining patients (P 5 .004). Overall survival
and disease-free survival were also significantly longer for
patients with LRP2/P-gp2 leukemias as compared to the
Table 3. LRP and P-Glycoprotein (P-gp) Status in Relation to
Outcome of Induction Chemotherapy
Total
LRP2/P-gp2
LRP1/P-gp2 or
LRP2/P-gp1
LRP1/P-gp1
No. of
Patients
Complete
Remission
Resistant
Disease
Early
Death
Not
Evaluable
82
49
59 (72%)
41 (84%)
9 (11%)
4 (8%)
10 (12%)
3 (6%)
4 (5%)
1 (2%)
28
5
16 (57%)
2 (40%)
3 (11%)
2 (40%)
6 (21%)
1 (20%)
3 (11%)
0 (0%)
LRP and P-gp expression of leukemic blasts was determined as
described in Patients and Methods. Induction chemotherapy included
MDR drugs (daunorubicin, etoposide) in most patients. Response to
induction chemotherapy was assessed according to standard criteria.
Response data are shown for patients without expression of these two
genes, for patients with expression of either of these genes, and for
patients with expression of both genes. Statistical analysis (chisquared test) for complete remission: P 5 .004.
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
1512
FILIPITS ET AL
remaining patients with a median overall survival of 24 versus 7
months (P 5 .0002) and a median disease-free survival of 9
versus 6 months (P 5 .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.
REFERENCES
1. Pastan I, Gottesman M: Multiple-drug resistance in human cancer.
N Engl J Med 316:1388, 1987
2. Filipits M, Suchomel RW, Zöchbauer S, Malayeri R, Pirker R:
Clinical relevance of drug resistance genes in malignant diseases.
Leukemia 10:10, 1996 (suppl 3)
3. Cole SPC, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE,
Almquist KC, Stewart AJ, Kurz EU, Duncan AMV, Deeley RG:
Overexpression of a transporter gene in a multidrug-resistant human
lung cancer cell line. Science 258:1650, 1992
4. Grant CE, Valdimarsson G, Hipfner DR, Almquist KC, Cole SPC,
Deeley RG: Overexpression of multidrug resistance-associated protein
(MRP) increases resistance to natural product drugs. Cancer Res
54:357, 1994
5. Pirker R, Wallner J, Geissler K, Linkesch W, Haas OA, Bettelheim
P, Hopfner M, Scherrer R, Valent P, Havelec L, Ludwig H, Lechner K:
MDR1 gene expression and treatment outcome in acute myeloid
leukemia. J Natl Cancer Inst 83:708, 1991
6. Marie J-P, Zittoun R, Sikic BI: Multidrug resistance (mdr1) gene
expression in adult acute leukemias: Correlations with treatment
outcome and in vitro drug sensitivity. Blood 78:586, 1991
7. Campos L, Guyotat D, Archimbaud E, Calmard-Oriol P, Tsuruo T,
Troncy J, Treille D, Fiere D: Clinical significance of multidrug
resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79:473, 1992
8. Zöchbauer S, Gsur A, Brunner R, Kyrle PA, Lechner K, Pirker R:
P-glycoprotein expression as unfavorable prognostic factor in acute
myeloid leukemia. Leukemia 8:974, 1994
9. Filipits M, Suchomel RW, Zöchbauer S, Brunner R, Lechner K,
Pirker R: Multidrug resistance-associated protein (MRP) in acute
myeloid leukemia: No impact on treatment outcome. Clin Cancer Res
3:1419, 1997
10. Kuss BJ, Deeley RG, Cole SPC, Willman CL, Kopecky KJ,
Wolman SR, Eyre HJ, Lane SA, Nancarrow JK, Whitmore SA, Callen
DF: Deletion of gene for multidrug resistance in acute myeloid
leukaemia with inversion in chromosome 16: Prognostic implications.
Lancet 343:1531, 1994
11. Zöchbauer S, Haas OA, Schwarzinger I, Lechner K, Pirker R:
Multidrug resistance in acute myeloid leukaemia with inversion in
chromosome 16 or FAB M4Eo subtype. Lancet 344:894, 1994
12. Scheper RJ, Broxterman HJ, Scheffer GL, Kaaijk P, Dalton WS,
van Heijningen THM, van Kalken CK, Slovak ML, de Vries EGE, van
der Valk P, Meijer CJLM, Pinedo HM: Overexpression of a Mr 110,000
vesicular protein in non-P-glycoprotein-mediated multidrug resistance.
Cancer Res 53:1475, 1993
13. Scheffer GL, Wijngaard PLJ, Flens MJ, Izquierdo MA, Slovak
ML, Pinedo HM, Meijer CJLM, Clevers HC, Scheper RJ: The drug
resistance-related protein LRP is the human major vault protein. Nat
Med 1:578, 1995
14. Slovak ML, Pelkey Ho J, Cole SPC, Deeley RG, Greenberger L,
de Vries EGE, Broxterman HJ, Scheffer GL, Scheper RJ: The LRP gene
encoding a major vault protein associated with drug resistance maps
proximal to MRP on chromosome 16: Evidence that chromosome
breakage plays a key role in MRP or LRP gene amplification. Cancer
Res 55:4214, 1995
15. Kedersha NL, Miquel M-C, Bittner D, Rome LH: Vaults. II.
Ribonucleoprotein structures are highly conserved among higher and
lower eukaryotes. J Cell Biol 110:895, 1990
16. Rome L, Kedersha N, Chugani D: Unlocking vaults: Organelles
in search of a function. Trends Cell Biol 1:47, 1991
17. Izquierdo MA, Shoemaker RH, Flens MJ, Scheffer GL, Wu L,
Prather TR, Scheper RJ: Overlapping phenotypes of multidrug resistance among panels of human cancer-cell lines. Int J Cancer 65:230,
1996
18. Izquierdo MA, Scheffer GL, Flens MJ, Giaccone G, Broxterman
HJ, Meijer CJLM, van der Valk P, Scheper RJ: Broad distribution of the
multidrug resistance-related vault lung resistance protein in normal
human tissues and tumors. Am J Pathol 148:877, 1996
19. Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K,
Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR,
Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
LRP IN AML
HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J,
Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan
SK: Treatment of acute myelocytic leukemia: A study by Cancer and
Leukemia Group B. Blood 58:1203, 1981
20. Haas OA, Schwarzmeier JD, Nacheva E, Fischer P, Paietta E:
Investigations on karyotype evolution in patients with chronic myeloid
leukemia (CML). Blut 48:33, 1984
21. Kaplan EL, Meier P: Nonparametric estimation from incomplete
observations. J Am Stat Assoc 53:457, 1958
22. List AF, Spier CS, Grogan TM, Johnson C, Roe DJ, Greer JP,
Wolff SN, Broxterman HJ, Scheffer GL, Scheper RJ, Dalton WS:
Overexpression of the major vault transporter protein lung-resistance
protein predicts treatment outcome in acute myeloid leukemia. Blood
87:2464, 1996
23. Ghaddar HM, Plunkett W, Kantarjian HM, Pierce S, Freireich
1513
EJ, Keating MJ, Estey EH: Long-term results following treatment of
newly-diagnosed acute myelogenous leukemia with continuousinfusion high-dose cytosine arabinoside. Leukemia 8:1269, 1994
24. Izquierdo MA, van der Zee AGJ, Vermorken JB, van der Valk P,
Belien JAM, Giaccone G, Scheffer GL, Flens MJ, Pinedo HM,
Kenemans P, Meijer CJLM, de Vries EGE, Scheper RJ: Drug resistanceassociated marker Lrp for prediction of response to chemotherapy and
prognoses in advanced ovarian carcinoma. J Natl Cancer Inst 87:1230,
1995
25. Lum BL, Fisher GA, Brophy NA, Yahanda AM, Adler KM,
Kaubisch S, Halsey J, Sikic BI: Clinical trials of modulation of
multidrug resistance. Cancer 72:3502, 1993
26. Pirker R, Keilhauer G, Raschack M, Lechner C, Ludwig H:
Reversal of multi-drug resistance in human KB cell lines by structural
analogs of verapamil. Int J Cancer 45:916, 1990
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
1998 91: 1508-1513
Expression of the Lung Resistance Protein Predicts Poor Outcome in De
Novo Acute Myeloid Leukemia
Martin Filipits, Gudrun Pohl, Thomas Stranzl, Ralf W. Suchomel, Rik J. Scheper, Ulrich Jäger, Klaus
Geissler, Klaus Lechner and Robert Pirker
Updated information and services can be found at:
http://www.bloodjournal.org/content/91/5/1508.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.