Introduction: Approximately 45% of adults with acute myeloid leukemia (AML) have normal karyotypes and therefore lack structural abnormalities that can assist in the localization and characterization of molecular defects. The current study attempted to evaluate the potential prognostic role of multidrug resistance (MDR), regarded as one of the potential prognostic factors for the outcome of overall AML, for AML with normal karyotypes. Method and Materials: A functional MDR assay was performed in pretreatment samples from AML patients with normal karyotypes. The complete remission (CR) rate, event-free survival (EFS), and overall survival (OS) were analyzed according to the MDR status and clinical prognostic factors for 88 patients with AML with normal karyotypes. Results: MDR by efflux was expressed in 14 out of 48 evaluable patients (29%) but failed to identify the association with CR (p = 0.124). However, MDR was identified as an independent prognostic factor for EFS and OS (p = 0.013 and 0.046) together with the use of stem cell transplantation (p = 0.009 for EFS and 0.029 for OS) and the WBC count at presentation (p = 0.023 for EFS and 0.034 for OS). Conclusion: The functional MDR assay may provide information on the prognosis of AML patients with normal karyotypes, and it might be a possible guideline for risk-stratified treatment strategies in AML with normal karyotypes.

1.
Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, McCredie KB, Gehan EA, Freireich EJ: Cytogenetic pattern in acute myelogenous leukemia: A major reproducible determinant of outcome. Leukemia 1988;2:403–412.
2.
Schiffer CA, Lee EJ, Tomiyasu T, Wiernik PH, Testa JR: Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia. Blood 1989;73:263–270.
3.
Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325–4336.
4.
Casas S, Aventin A, Nomdedeu J, Sierra J: Cryptic t(5;11)(q35;p15.5) in adult de novo acute myelocytic leukemia with normal karyotype. Cancer Genet Cytogenet 2003;145:183.
5.
Brown J, Jawad M, Twigg SR, Saracoglu K, Sauerbrey A, Thomas AE, Eils R, Harbott J, Kearney L: A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay. Blood 2002;99:2526–2531.
6.
Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F, Knuutila S, Mrozek K, Oberkircher AR, Marcucci G, de la Chapelle A, Elonen E, Block AW, Rao PN, Herzig GP, Powell BL, Ruutu T, Schiffer CA, Bloomfield CD: Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 1998;58:55–59.
7.
Laupeze B, Amiot L, Drenou B, Bernard M, Branger B, Grosset JM, Lamy T, Fauchet R, Fardel O: High multidrug resistance protein activity in acute myeloid leukaemias is associated with poor response to chemotherapy and reduced patient survival. Br J Haematol 2002;116:834–838.
8.
Wuchter C, Leonid K, Ruppert V, Schrappe M, Buchner T, Schoch C, Haferlach T, Harbott J, Ratei R, Dorken B, Ludwig WD: Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia. Haematologica 2000;85:711–721.
9.
Guerci A, Merlin JL, Missoum N, Feldmann L, Marchal S, Witz F, Rose C, Guerci O: Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry. Blood 1995;85:2147–2153.
10.
Damiani D, Michelutti A, Michieli M, Masolini P, Stocchi R, Geromin A, Ermacora A, Russo D, Fanin R, Baccarani M: P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia. Br J Haematol 2002;116:519–527.
11.
Mitelman F: International System for Human Cytogenetic Nomenclature (1995) ISCN (1995). Basel, Karger, 1995.
12.
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998;92:2322–2333.
13.
Veldman T, Vignon C, Schrock E, Rowley JD, Ried T: Hidden chromosome abnormalities in haematological malignancies detected by multicolour spectral karyotyping. Nat Genet 1997;15:406–410.
14.
Zhang FF, Murata-Collins JL, Gaytan P, Forman SJ, Kopecky KJ, Willman CL, Appelbaum FR, Slovak ML: Twenty-four-color spectral karyotyping reveals chromosome aberrations in cytogenetically normal acute myeloid leukemia. Genes Chromosomes Cancer 2000;28:318–328.
15.
Romana SP, Mauchauffe M, Le Coniat M, Chumakov I, Le Paslier D, Berger R, Bernard OA: The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood 1995;85:3662–3670.
16.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000;96:4075–4083.
17.
Lemez P, Galikova J, Haas T: Do de novo acute myeloid leukemias with normal cytogenetics involve two main prognostic categories distinguished by the presence of erythroblastic and/or megakaryocytic dysplasia? Neoplasma 2000;47:41–47.
18.
Del Poeta G, Venditti A, Stasi R, Aronica G, Cox MC, Buccisano F, Tamburini A, Bruno A, Maurillo L, Battaglia A, Suppo G, Epiceno AM, Del Moro B, Masi M, Amadori S, Papa G: P-glycoprotein and terminal transferase expression identify prognostic subsets within cytogenetic risk classes in acute myeloid leukemia. Leuk Res 1999;23:451–465.
19.
Ye X, Tan H, Feng Y, Su H, Lai YY, Pang Y: Significance of functional assay of multidrug resistance for prediction of chemotherapy outcomes in acute leukemia. Ai Zheng 2003;22:856–860.
20.
Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001;98:1752–1759.
21.
Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, Wermke M, Bornhauser M, Ritter M, Neubauer A, Ehninger G, Illmer T: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002;99:4326–4335.
22.
Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K: Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML Study Group Ulm. Blood 2002;100:4372–4380.
23.
Andersson A, Johansson B, Lassen C, Mitelman F, Billstrom R, Fioretos T: Clinical impact of internal tandem duplications and activating point mutations in FLT3 in acute myeloid leukemia in elderly patients. Eur J Haematol 2004;72:307–313.
24.
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: FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: Prognostic significance and relation to cellular drug resistance. Blood 2003;102:2387–2394.
25.
Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaum FR, Willman CL: Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group Study. Blood 1997;89:3323–3329.
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2005
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