Submitted November 21, 2008
Accepted June 1, 2009
Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia
Marc Ansari, Geraldine Sauty, Malgorzata Labuda, Vincent Gagne, Caroline Laverdiere, Albert Moghrabi, Daniel Sinnett, and Maja Krajinovic*
Research Center, CHU Sainte-Justine, Montreal, QC, Canada
Department of Pediatrics, University of Montreal, Montreal, QC, Canada
Department of Pharmacology, University of Montreal, Montreal, QC, Canada
* Corresponding author; email: maja.krajinovic{at}umontreal.ca.
Methotrexate (MTX) and 6-mercaptopurine, important components of acute lymphoblastic leukemia (ALL) treatment, are substrates for multidrug resistance associated protein MRP4. Eight single nucleotide polymorphisms (SNP) were analyzed in MRP4 gene and four variants were identified as tagSNPs with frequency 
5%. They were investigated for association with treatment responses in 275 children with ALL. The TC genotype of the regulatory T-1393C polymorphism was associated with better event free survival (EFS, p=0.02) and lower MTX plasma levels (p=0.01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower EFS (p=0.02) and higher frequency of high-grade thrombocytopenia (p=0.01). Gene reporter assay showed that the promoter haplotype uniquely tagged by C-1393 allele conferred higher promoter activity in comparison to remaining haplotypes (p<0.0001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.
