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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.