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Title

Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia

Authors
Sauty, Géraldine
Labuda, Malgorzata
Gagné, Vincent
Laverdière, Caroline
Moghrabi, Albert
Sinnett, Daniel
Krajinovic, Maja
Published in Blood. 2009, vol. 114, no. 7, p. 1383-6
Abstract Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P = .02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.
Keywords 6-Mercaptopurine/therapeutic useAdolescentAllelesAmino Acid SubstitutionAntimetabolites, Antineoplastic/therapeutic useChildChild, PreschoolDisease-Free SurvivalFemaleGene FrequencyGenotypeHumansMaleMethotrexate/therapeutic useMultidrug Resistance-Associated Proteins/geneticsMutation, MissensePilot ProjectsPolymorphism, Single NucleotidePrecursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/mortalityPromoter Regions, Genetic/geneticsRetrospective StudiesSurvival Rate
Identifiers
PMID: 19515727
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Article (Published version) (338 Kb) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Plateforme d'oncologie et d'hématologie pédiatrique (907)
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ANSARI DJABERI, Marc Georges et al. Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. In: Blood, 2009, vol. 114, n° 7, p. 1383-6. https://archive-ouverte.unige.ch/unige:43455

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Deposited on : 2014-12-15

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