The Lung Resistance Protein (LRP) Predicts Poor Outcome in Acute Myeloid Leukemia

  • Robert Pirker
  • Gudrun Pohl
  • Thomas Stranzl
  • Ralf W. Suchomel
  • Rik J. Scheper
  • Ulrich Jäger
  • Klaus Geissler
  • Klaus Lechner
  • Martin Filipits
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 457)

Abstract

To determine the clinical significance of the lung resistance protein (LRP) in acute myeloid leukemia (AML), we have studied LRP expression of leukemic blasts and its association with clinical outcome in patients with de novo AML. LRP expression of leukemic blasts was determined by immunocytochemistry by means of monoclonal antibody LRP-56. LRP expression at diagnosis was detected in 31 out of 86 (36%) patients and correlated with white blood cell count (p = 0.01). The complete remission rate of induction chemotherapy was 72% for all treated patients (n = 82). The complete remission rate was 81% for patients without LRP expression but only 55% for patients with LRP expression (p = 0.01). Overall survival and disease-free survival were estimated according to Kaplan-Meier in 82 and 59 patients, respectively. At a median follow-up of 16 months, median overall survival was 17 months for LRP-negative patients but only 8 months for LRP-positive patients (p = 0.006). Disease-free survival was 9 months for LRP-negative patients and 6 months for LRP-positive patients (p = 0.078). Thus LRP predicts for poor outcome indicating that the LRP gene is a clinically relevant drug resistance gene in AML.

Keywords

lung resistance protein LRP drug resistance acute myeloid leukemia prognosis 
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References

  1. 1.
    Pastan I, Gottesman M. Multiple-drug resistance in human cancer. N Engl J Med 1987, 316, 1388–1393PubMedCrossRefGoogle Scholar
  2. 2.
    Filipits M, Suchomel RW, Zöchbauer S, Malayeri R, Pirker R. Clinical relevance of drug resistance genes in malignant diseases. Leukemia 1996, 10(Suppl. 3), 10–17Google Scholar
  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 1992, 258, 1650–1654PubMedCrossRefGoogle Scholar
  4. 4.
    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 1991, 83, 708–712PubMedCrossRefGoogle Scholar
  5. 5.
    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 1991, 78, 586–592PubMedGoogle Scholar
  6. 6.
    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 1992, 79, 473–476PubMedGoogle Scholar
  7. 7.
    Zöchbauer S, Gsur A, Brunner R, Kyrle PA, Lechner K, Pirker R. P-glycoprotein expression as unfavorable prognostic factor in acute myeloid leukemia. Leukemia 1994, 8, 974–977PubMedGoogle Scholar
  8. 8.
    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 1997, 3, 1419–1425PubMedGoogle Scholar
  9. 9.
    Filipits M, Stranzl T, Pohl G, Suchomel RW, Zöchbauer S, Brunner R, Lechner K, Pirker R. MRP expression in acute myeloid leukemia: an update. This volume (Chapter 16)Google Scholar
  10. 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 1994, 343, 1531–1534PubMedCrossRefGoogle Scholar
  11. 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 1994, 344, 894PubMedCrossRefGoogle Scholar
  12. 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 1993, 53, 1475–1479PubMedGoogle Scholar
  13. 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 1995, 1, 578–582PubMedCrossRefGoogle Scholar
  14. 14.
    Kedersha NL, Miquel M-C, Bittner D, Rome LH. Vaults. II. Ribonucleoprotein structures are highly conserved among higher and lower eukaryotes. J Cell Biol 1990, 110, 895–901PubMedCrossRefGoogle Scholar
  15. 15.
    Rome L, Kedersha N, Chugani D: Unlocking vaults: organelles in search of a function. Trends Cell Biol 1991, 1, 47–50PubMedCrossRefGoogle Scholar
  16. 16.
    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 1996, 65, 230–237PubMedCrossRefGoogle Scholar
  17. 17.
    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 1996, 148, 877–887PubMedGoogle Scholar
  18. 18.
    Filipits M, Pohl G, Stranzl T, Suchomel RW, Scheper RJ, Jäger U, Geissler K, Lechner K, Pirker R. Expression of the lung resistance protein predicts poor outcome in de novo acute myeloid leukemia. Blood 1998, 91, 1508–1513PubMedGoogle Scholar
  19. 19.
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958, 53, 457–481CrossRefGoogle Scholar
  20. 20.
    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 1996, 87, 2464–2469PubMedGoogle Scholar
  21. 21.
    Ghaddar HM, Plunkett W, Kantarjian HM, Pierce S, Freireich EJ, Keating MJ, Estey EH. Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside. Leukemia 1994, 8, 1269–1274PubMedGoogle Scholar
  22. 22.
    Lum BL, Fisher GA, Brophy NA, Yahanda AM, Adler KM, Kaubisch S, Halsey J, Sikic BI. Clinical trials of modulation of multidrug resistance. Cancer 1993, 72, 3502–3514PubMedCrossRefGoogle Scholar
  23. 23.
    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 1990, 45, 916–919PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Robert Pirker
    • 1
  • Gudrun Pohl
    • 1
  • Thomas Stranzl
    • 1
  • Ralf W. Suchomel
    • 1
  • Rik J. Scheper
    • 1
    • 2
  • Ulrich Jäger
    • 1
  • Klaus Geissler
    • 1
  • Klaus Lechner
    • 1
  • Martin Filipits
    • 1
  1. 1.Divisions of Oncology and Hematology Department of Internal Medicine IUniversity of Vienna Medical SchoolViennaAustria
  2. 2.Department of PathologyFree University HospitalAmsterdamThe Netherlands

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