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MDR-1 and GST polymorphisms are involved in myelodysplasia progression

Bruna Palodetto1, Paula de Melo Campos, Bruno Deltreggia Benites

  • 1Laboratory of Biochemistry, Molecular and Cell Biology, Hematology and Hemotherapy Center Campinas, University of Campinas/Hemocentro Campinas-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. brunapalodetto@hotmail.com

Leukemia Research
|May 21, 2013
PubMed

Insights

Genetic variations in drug-metabolizing enzymes like Glutathione S-transferase (GST) and P-glycoprotein (MDR-1) influence myelodysplastic syndromes (MDS) progression. GST deletions and MDR-1 CC genotype were linked to a higher risk of MDS progression.

Area of Science:

  • Hematology
  • Pharmacogenetics
  • Molecular Biology

Background:

  • Myelodysplastic syndromes (MDS) are clonal stem cell disorders with a risk of progressing to acute leukemia.
  • Drug metabolism gene polymorphisms, including Cytochrome P450 2B6 (CYP2B6), Glutathione S-transferase (GST), Dehydrogenase Quinone 1 (NQO1), and P-glycoprotein (MDR-1), can affect disease outcomes.
  • Understanding these genetic influences is crucial for predicting MDS progression.

Purpose of the Study:

  • To investigate the impact of specific genetic polymorphisms (CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T, MDR-1 C3435T) on the progression of myelodysplastic syndromes.
  • To determine if these polymorphisms are associated with overall survival in MDS patients.

Main Methods:

  • Analysis of 78 MDS patients using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and multiplex methods.
  • Genotyping for CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T, and MDR-1 C3435T polymorphisms.
  • Statistical analysis to correlate genotypes with MDS progression and overall survival.

Main Results:

  • GST deletions and the MDR-1 CC genotype were significantly more frequent in patients with MDS progression compared to those without progression (GST: 35% vs. 17%, P=0.018; MDR-1: 48% vs. 19%, P=0.012).
  • No significant association was found between these polymorphisms and overall patient survival.
  • GSTM1 deletion may increase MDS progression risk, potentially via toxic metabolite accumulation and DNA damage.

Conclusions:

  • GSTM1 deletion is implicated as a risk factor for MDS progression, possibly due to enhanced cellular toxicity.
  • The MDR-1 C3435T polymorphism might offer a protective effect against MDS progression by potentially increasing P-glycoprotein-mediated cell death.
  • This study provides novel insights into the role of pharmacogenetic polymorphisms in MDS progression.

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