title: MDR-1 and GST polymorphisms are involved in myelodysplasia progression.
abstract: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by abnormal hematopoietic differentiation and maturation, which progress toward acute leukemia in approximately 30% of the cases. Drug metabolism polymorphisms in Cytochrome P450 2B6 (CYP2B6), Glutathione S-transferase (GST) and Dehydrogenase Quinone 1 (NQO1) enzymes and P-glycoprotein (MDR-1) could modify enzyme activity. Thus, the aim of this study was to identify the influence of CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T and MDR-1 C3435T polymorphisms on MDS progression. We analyzed 78 MDS patients using the PCR-RFLP and multiplex method. The frequency of GST deletions and MDR-1 CC genotype was lower in progression-free patients compared to patients with progression; GST: 17% vs. 35% (P=0.018); MDR-1 gene: 19% vs. 48% (P=0.012). We also verified the influence of GST deletions and MDR-1 C3435T on patient overall survival and found no significant difference (RR=0.75; P=0.599 and RR=0.79; P=0.594 respectively). We concluded that GSTM1 deletion may contribute toward MDS progression probably due to toxic metabolite accumulation which generates cell toxicity and DNA damage. Moreover, MDR-1 C3435T may have a protective effect against MDS progression because the expected lower expression of P-glycoprotein would lead to a higher degree of cell death. To the best of our knowledge, this is the first study showing the relationship of these polymorphisms with MDS progression.
authors.affiliation: Laboratory of Biochemistry, Molecular and Cell Biology, Hematology and Hemotherapy Center Campinas, University of Campinas/Hemocentro Campinas-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. brunapalodetto@hotmail.com
authors.forename: Bruna
authors.initials: B
authors.lastname: Palodetto
authors.forename: Paula
authors.initials: P
authors.lastname: de Melo Campos
authors.forename: Bruno Deltreggia
authors.initials: BD
authors.lastname: Benites
authors.forename: Maria
authors.initials: M
authors.lastname: de Lourdes Lopes Ferrari Chauffaille
authors.forename: Elvira Deolinda Rodrigues Pereira
authors.initials: ED
authors.lastname: Velloso
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.forename: Sara Teresinha Olalla
authors.initials: ST
authors.lastname: Saad
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001483:Base Sequence; D065702:Cytochrome P-450 CYP2B6; D018450:Disease Progression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D016016:Proportional Hazards Models; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D005982:Glutathione Transferase; D016660:NAD(P)H Dehydrogenase (Quinone); D010089:Oxidoreductases, N-Demethylating; C513055:ABCB1 protein, human; C585599:CYP2B6 protein, human; C447479:NQO1 protein, human; C413545:glutathione S-transferase T1