Laboratory 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.
Leuk Res. 2013 Aug;37(8):970-3. doi: 10.1016/j.leukres.2013.04.024. Epub 2013 May 17.
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by abnormal hematopoietic differentiation and maturation, which progress toward acute leukemia in approximately 30% of the cases. Drug metabolism polymorphisms in Cytochrome P450 2B6 (CYP2B6), Glutathione S-transferase (GST) and Dehydrogenase Quinone 1 (NQO1) enzymes and P-glycoprotein (MDR-1) could modify enzyme activity. Thus, the aim of this study was to identify the influence of CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T and MDR-1 C3435T polymorphisms on MDS progression. We analyzed 78 MDS patients using the PCR-RFLP and multiplex method. The frequency of GST deletions and MDR-1 CC genotype was lower in progression-free patients compared to patients with progression; GST: 17% vs. 35% (P=0.018); MDR-1 gene: 19% vs. 48% (P=0.012). We also verified the influence of GST deletions and MDR-1 C3435T on patient overall survival and found no significant difference (RR=0.75; P=0.599 and RR=0.79; P=0.594 respectively). We concluded that GSTM1 deletion may contribute toward MDS progression probably due to toxic metabolite accumulation which generates cell toxicity and DNA damage. Moreover, MDR-1 C3435T may have a protective effect against MDS progression because the expected lower expression of P-glycoprotein would lead to a higher degree of cell death. To the best of our knowledge, this is the first study showing the relationship of these polymorphisms with MDS progression.
骨髓增生异常综合征（MDS）是一组异质性克隆性干细胞疾病，其特征为造血分化和成熟异常，约 30%的病例进展为急性白血病。细胞色素 P450 2B6（CYP2B6）、谷胱甘肽 S-转移酶（GST）和醌氧化还原酶 1（NQO1）酶和 P-糖蛋白（MDR-1）的药物代谢多态性可改变酶活性。因此，本研究旨在确定 CYP2B6 G15631T、GSTT1、GSTM1、NQO1 C609T 和 MDR-1 C3435T 多态性对 MDS 进展的影响。我们使用 PCR-RFLP 和多重方法分析了 78 例 MDS 患者。无进展患者 GST 缺失和 MDR-1 CC 基因型的频率低于进展患者；GST：17%比 35%（P=0.018）；MDR-1 基因：19%比 48%（P=0.012）。我们还验证了 GST 缺失和 MDR-1 C3435T 对患者总生存的影响，未发现显著差异（RR=0.75；P=0.599 和 RR=0.79；P=0.594）。我们得出结论，GSTM1 缺失可能导致 MDS 进展，可能是由于有毒代谢物的积累导致细胞毒性和 DNA 损伤。此外，MDR-1 C3435T 可能对 MDS 进展具有保护作用，因为预期较低的 P-糖蛋白表达会导致更高程度的细胞死亡。据我们所知，这是第一项显示这些多态性与 MDS 进展之间关系的研究。
