Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia
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Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53 proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemia.
Total number of 787 children diagnosed for initial ALL (n = 527), relapsed ALL (n = 104), initial AML (n = 133) and relapsed AML (n = 23) were included into the study. Mean follow-up period was 3.5 years. Drug resistance for up to 30 anticancer agents was performed by the MTT assay. Expression of all proteins was tested by flow cytometry.
Both initial AML and relapsed ALL samples showed higher drug resistance than initial ALL samples. No significant differences were found in drug resistance between initial and relapsed AML samples. The presence of multidrug resistance and apoptosis proteins had no impact on pDFS in iALL and iAML, however strong trend towards adverse prognostic impact of MRP1, PGP and LRP on pDFS in rALL was observed. The same trend was observed for each of analyzed co-expressions of tested multidrug resistance proteins.
The phenomenon of cellular drug resistance in childhood acute leukemias is multifactorial and plays an important role in response to therapy. Expression of MRP1, PGP and LRP proteins, as well as their co-expression play possible role in childhood relapsed ALL.
KeywordsAcute lymphoblastic leukemia Acute myelogenous leukemia Relapse PGP MRP1 LRP Drug resistance
The authors thank the anonymous reviewers for their effort to improve quality of this paper. This study was supported by grants KBN 6 PO5E 082 21 and N407 078 32/2964.
- Borowitz MJ, Pullen DJ, Shuster JJ, Viswanatha D, Montgomery K, Willman CL, Camitta B (2003) Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children’s Oncology Group study. Leukemia 17:1566–1572PubMedCrossRefGoogle Scholar
- Den Boer ML, Pieters R, Kazemier KM, Rottier MM, Zwaan CM, Kaspers GJ, Janka-Schaub G, Henze G, Creutzig U, Scheper RJ, Veerman AJ (1998) Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. Blood 91:2092–2098Google Scholar
- Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE, Henze G, Creutzig U, Kaspers GJ, Kearns PR, Hall AG, Pearson AD, Veerman AJ (1999b) Different expression of glutathione S-transferase alpha, mu and pi in childhood acute lymphoblastic and myeloid leukaemia. Br J Haematol 104:321–327CrossRefGoogle Scholar
- Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE, Henze G, Veerman AJ (1999c) Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. Leukemia 13:2023–2030CrossRefGoogle Scholar
- Den Boer ML, Harms DO, Pieters R, Kazemier KM, Gobel U, Korholz D, Graubner U, Haas RJ, Jorch N, Spaar HJ, Kaspers GJ, Kamps WA, Van der Does-Van den Berg A, Van Wering ER, Veerman AJ, Janka-Schaub GE (2003) Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. J Clin Oncol 21:3262–3268CrossRefGoogle Scholar
- Dluzniewska A, Balwierz W, Armata J, Balcerska A, Chybicka A, Kowalczyk J, Matysiak M, Ochocka M, Radwanska U, Rokicka-Milewska R, Sonta-Jakimczyk D, Wachowiak J, Wysocki M (2005) Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia. Leukemia 19:2117–2124PubMedCrossRefGoogle Scholar
- Einsiedel HG, von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G, Mann G, Hahlen K, Gobel U, Klingebiel T, Ludwig WD, Henze G (2005) Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J Clin Oncol 23:7942–7950PubMedCrossRefGoogle Scholar
- Fleischhack G, Hasan C, Graf N, Mann G, Bode U (1998) IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial. Br J Haematol 102:647–655PubMedCrossRefGoogle Scholar
- Ikeda K, Oka M, Yamada Y, Soda H, Fukuda M, Kinoshita A, Tsukamoto K, Noguchi Y, Isomoto H, Takeshima F, Murase K, Kamihira S, Tomonaga M, Kohno S (1999) Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP) and lung-resistance-protein (LRP) genes. Int J Cancer 82:599–604PubMedCrossRefGoogle Scholar
- Kardos G, Zwaan CM, Kaspers GJ, de-Graaf SS, de Bont ES, Postma A, Bokkerink JP, Weening RS, van der Does-van den Berg A, van Wering ER, Korbijn C, Hahlen K (2005) Treatment strategy and results in children treated on three Dutch Childhood Oncology Group acute myeloid leukemia trials. Leukemia 19:2063–2071PubMedCrossRefGoogle Scholar
- Kasimir-Bauer S, Ottinger H, Meusers P, Beelen DW, Brittinger G, Seeber S, Scheulen ME (1998) In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy. Exp Hematol 26:1111–1117PubMedGoogle Scholar
- Kasimir-Bauer S, Beelen D, Flasshove M, Noppeney R, Seeber S, Scheulen ME (2002) Impact of the expression of P glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat shock protein 27 on response to induction therapy and long-term survival in patients with de novo acute myeloid leukemia. Exp Hematol 30:1302–1308PubMedCrossRefGoogle Scholar
- Plasschaert S, Vellenga E, De Bont E, Van der Kolk D, Veerman A, Sluiter W, Daenen S, De Vries E, Kamps WA (2003) High functional P-glycoprotein activity is more often present in T-cell acute lymphoblastic leukaemic cells in adults than in children. Leuk Lymphoma 44:85–95PubMedCrossRefGoogle Scholar
- Ramakers-van Woerden NL, Pieters R, Hoelzer D, Slater RM, den Boer ML, Loonen AH, Harbott J, Janka-Schaub GE, Ludwig WD, Ossenkoppele GJ, van Wering ER, Veerman AJ (2002) In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups. Med Pediatr Oncol 38:379–386PubMedCrossRefGoogle Scholar
- Riehm H, Reiter A, Schrappe M, Berthold F, Dopfer R, Gerein V, Ludwig R, Ritter J, Stollmann B, Henze G (1987) Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83). Klin Padiatr 199:151–160PubMedCrossRefGoogle Scholar
- Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H (2000a) Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95:3310–3322PubMedGoogle Scholar
- Steinbach D, Wittig S, Cario G, Viehmann S, Mueller A, Gruhn B, Haefer R, Zintl F, Sauerbrey A (2003b) The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype. Blood 102:4493–4498PubMedCrossRefGoogle Scholar
- Styczynski J, Wysocki M, Debski R, Juraszewska E, Malinowska I, Stanczak E, Ploszynska A, Stefaniak J, Mazur B, Szczepanski T (2002) Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia. Leuk Lymphoma 43:1843–1848PubMedCrossRefGoogle Scholar
- van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig WD, Basso G, de Bruijn MA, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WC, Riehm H, Bartram CR (1998) Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352:1731–1738PubMedCrossRefGoogle Scholar
- Wysocki M, Styczynski J, Debski R, Kubicka M, Balwierz W, Juraszewska E, Rokicka-Milewska R, Malinowska I, Matysiak M, Stanczak E, Balcerska A, Ploszynska A, Kowalczyk JR, Stefaniak J, Malek U, Wachowiak J, Mazur B, Sonta-Jakimczyk D, Szczepanski T, Chybicka A, Ras M (2002) Drug resistance profile in childhood acute lymphoblastic leukemia on diagnosis and at relapse with respect to percentile values. Report of Polish Pediatric Leukemia and Lymphoma Study Group. Acta Haematol Pol 33:341–350Google Scholar
- Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR (2002) Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1:133–143PubMedCrossRefGoogle Scholar
- Zhao Y, Yu L, Lou F, Wang Q, Pu J, Zhou Q (1999) [The clinical significance of lung resistance-related protein gene (lrp), multidrug resistance-associated protein gene (mrp) and mdr-1/p170 expression in acute leukemia]. Zhonghua Nei Ke Za Zhi38:760–763Google Scholar
- Zwaan CM (2003) Prognostic factors in AML. In: Toward subgroup-directed therapy in acute myeloid leukemia, Vrije Univeristeit. Amsterdam, pp 24–26Google Scholar
- Zwaan CM, Kaspers GJ, Pieters R, Ramakers-Van Woerden NL, den Boer ML, Wunsche R, Rottier MM, Hahlen K, van Wering ER, Janka-Schaub GE, Creutzig U, Veerman AJ (2000) Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia. Blood 96:2879–2886PubMedGoogle Scholar
- Zwaan CM, Meshinchi S, Radich JP, Veerman AJ, Huismans DR, Munske L, Podleschny M, Hahlen K, Pieters R, Zimmermann M, Reinhardt D, Harbott J, Creutzig U, Kaspers GJ, Griesinger F (2003) FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 102:2387–2394PubMedCrossRefGoogle Scholar