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 Blood, 13 August 2009, Vol. 114, No. 7, pp. 1383-1386.
Prepublished online as a Blood First Edition Paper on June 10, 2009; DOI 10.1182/blood-2008-11-191098.

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LYMPHOID NEOPLASIA

Brief Report

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

Marc Ansari1,2, Géraldine Sauty1, Malgorzata Labuda1, Vincent Gagné1, Caroline Laverdière1,3, Albert Moghrabi1,3, Daniel Sinnett1,3, and Maja Krajinovic1,3,4

1 Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC; 2 Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland; and Departments of 3 Pediatrics and 4 Pharmacology, University of Montreal, Montreal, QC

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.


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