Journal
BLOOD
Volume 114, Issue 7, Pages 1383-1386Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-11-191098
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Funding
- Leukemia-Lymphoma Society of Canada
- Canadian Institute of Health Research
- Research Center of Centre Hospitalier Universitaire Sainte-Justine
- Charles Bruneau Foundation
- Center d'excellence en Oncologie pediatrique et en soins palliatifs
- Swiss National Fund
- Charles Bruneau and Telemaque foundation
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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. (Blood. 2009;114:1383-1386)
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