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

Marc Ansari1, Géraldine Sauty, Malgorzata Labuda

  • 1Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.

Blood
|June 12, 2009
PubMed

Insights

Genetic variations in the MRP4 gene impact acute lymphoblastic leukemia treatment. Specific MRP4 gene variants are linked to patient outcomes and drug levels, suggesting a role in treatment response.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Molecular Biology

Background:

  • Methotrexate and 6-mercaptopurine are key drugs for acute lymphoblastic leukemia (ALL).
  • Multidrug resistance-associated protein 4 (MRP4) transports these drugs, influencing their efficacy and toxicity.
  • Genetic variations in MRP4 may affect its function and consequently, treatment outcomes in ALL patients.

Purpose of the Study:

  • To investigate the association between single nucleotide polymorphisms (SNPs) in the MRP4 gene and treatment response in children with ALL.
  • To identify specific MRP4 variants that correlate with event-free survival, drug plasma levels, and adverse events.

Main Methods:

  • Analysis of eight tagSNPs in the MRP4 gene from a cohort of 275 children with ALL.
  • Statistical analysis to correlate genotypes with event-free survival, methotrexate plasma levels, and thrombocytopenia.
  • Gene reporter assays to assess the functional impact of promoter polymorphisms on gene activity.

Main Results:

  • The TC genotype of the T-1393C polymorphism was associated with better event-free survival and lower methotrexate levels (P = .02 and P = .01, respectively).
  • The CA genotype of the A934C (Lys304Asn) substitution correlated with lower event-free survival and increased high-grade thrombocytopenia (P = .02 and P = .01, respectively).
  • A promoter haplotype tagged by the C-1393 allele showed significantly higher promoter activity (P < .001).

Conclusions:

  • Specific MRP4 gene polymorphisms are associated with differential treatment responses in pediatric acute lymphoblastic leukemia.
  • These findings highlight the potential role of MRP4 pharmacogenetics in personalizing ALL therapy.
  • Further studies are warranted to confirm these results and elucidate the functional mechanisms involved.

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