Original Article Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia
Shalaka S. Hampras, Lara Sucheston, Joli Weiss, Maria R. Baer, Gary Zirpoli, Prashant K. Singh, Meir Wetzler, Raj Chennamaneni, Javier G. Blanco, LaurieAnn Ford, Kirsten B. Moysich
Dept. of Neurology, University of Milan, Ospedale L. Sacco, Milan, Italy; Dept. of Neurological Sciences, "Dino Ferrari" Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy; Dept. of Neuroscience, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy; Section of Biochemistry, Faculty of Medicine, University of Brescia and III Laboratorio Analisi Chimico Cliniche, Spedali Civili di Brescia, Brescia, Italy; University of Maryland Greenebaum Center, Baltimore, MD, 21201, USA; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA; Department of Pharmaceutical Sciences, University at Buffalo, NY, 14214, USA; Department of Clinical Research Services, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
Received April 18, 2010, accepted May 17, 2010, available online May 20, 2010
Abstract: The overall survival of patients with acute myeloid leukemia (AML) remains poor due to both intrinsic and acquired chemotherapy resistance. Over expression of ATP binding cassette (ABC) proteins in AML cells has been suggested as a putative mechanism of drug resistance. Genetic variation among individuals affecting the expression or function of these proteins may contribute to inter-individual variation in treatment outcomes. DNA from pretreatment bone marrow or blood samples from 261 patients age 20-85 years, who received cytarabine and anthracycline- based therapy at Roswell Park Cancer Institute between 1994 and 2006, was genotyped for eight nonsynonymous single nucleotide polymorphisms in the ABCB1, ABCC1 and ABCG2 drug transporter genes. Heterozygous (AG) or homozygous (AA) variant genotypes for rs2231137 (G34A) in the ABCG2 (BRCP) gene, compared to the wild type (GG) genotype were associated with both significantly improved survival (HR=0.44, 95%CI=0.25-0.79), and increased odds for toxicity (OR=8.41, 95%CI=1.10-64.28). Thus genetic polymorphisms in the ABCG2 (BRCP) gene may contribute to differential survival outcomes and toxicities in AML patients via a mechanism of decreased drug efflux in both, AML cells and normal progenitors. (IJMEG1004002).