Negative impact of FLT3-ITD mutation on expression of MDR-1 mRNA in adult acute myeloid leukemia

Abstract

Th e treatment outcome of patients with acute myeloid leukemia (AML) varies considerably, and refl ects the heterogeneity of the disease. Although the development of new therapeutic agents and treatment regimens has improved the cure rate of patients with AML, from 20 to 50% of patients are primarily resistant to induction chemotherapy and most of the remaining will relapse and die of their disease. Outcomes are poor in part due to resistance to chemotherapeutic drugs. While some mechanisms of drug resistance have been well characterized, this phenomenon still remains incompletely understood. One mechanism behind drug resistance is altered drug transport, which could be due to overexpression of the transport proteins: p-glycoprotein (Pgp), multidrug resistance protein-1 (MRP-1), breast cancer resistance protein (BCRP) and lung resistance-related protein (LRP). Th ree of them – Pgp, MRP-1 and BCRP – are members of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily, and function as a membrane pump responsible for the effl ux of a range of chemotherapeutic drugs. Pgp is the protein product of the multidrug resistance-1 ( MDR-1 ) gene, and is still considered by many researchers as the prognostic marker and major determinant for poor outcomes in AML [1 – 4]. It was shown that Pgp also has an anti-apoptotic function in AML that is independent of its role in drug effl ux. Pgp can inhibit ceramide-mediated apoptosis [5]. Compounds that inhibit the effl ux function of Pgp in AML cells may also be active against its anti-apoptotic function. Th ere has been much recent interest in identifying new molecular markers of prognostic value in AML. Of these, internal tandem duplication (ITD) in the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) has been found to have a strong correlation with drug resistance and a poor outcome in about 30% of cases of AML [6]. It has been reported in some research articles that FLT3 -ITD may negatively infl uence MDR - 1 /Pgp expression in AML blasts [3,7,8]. Th is is of especial interest as MDR-1 /Pgp and FLT3 -ITD mutation are well known targets for inhibition by several agents tested in preclinical and clinical trials. In this study, we estimated the expression of MDR-1 , MRP-1 , BCRP and LRP mRNA and detected the FLT3 -ITD mutation in patients with AML. We divided all patients into two groups according to FLT3 -ITD mutation (positive and negative), and compared the expression of the tested genes and other prognostic factors in AML: age (� 60 vs. � 60 years), cytogenetic aberrations (good, intermediate, poor according to Southwest Oncology Group [SWOG] classifi cation), de novo /secondary AML, white blood cell count (WBC), the percentage of blasts in the bone marrow (BM) and peripheral blood (PB), and the type of AML according to the French – American – British (FAB) classifi cation between groups. Moreover, the rates of complete remission (CR) and relapse (RR), and disease-free survival (DFS) and overall survival (OS), in both groups were estimated. A total of 126 consecutive adult patients with a median age of 53 years (range 21 – 87), comprising 59 (46.8%) women and 67 (53.2%) men with previously untreated AML, newly diagnosed between June 2007 and March 2010, and 40 healthy donors were included in this study. Diagnosis of AML was based on standard morphological and immunophenotypic criteria in accordance with the World Health Organization (WHO) classifi cation. Baseline characteristics of patients are given in Table I.