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首页> 外文期刊>Pharmacogenetics >Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients.
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Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients.

机译：脱氧胞苷激酶中的单核苷酸多态性与急性髓细胞性白血病患者的治疗反应之间的关联。

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Development of resistance to 1-beta-arabinofuranosylcytosine (AraC) is a major obstacle in the treatment of patients with acute myeloid leukaemia (AML). Deficiency of functional deoxycytidine kinase (dCK) plays an important role in AraC resistance in vitro. We screened 5378 bp sequences of the dCK gene, including all exons and the 5' flanking region, and identified two single nucleotide polymorphisms (SNPs) in the regulatory region (rSNPs) with high allele frequencies. These two rSNPs (-201C>T and -360C>G) formed two major haplotypes. Genotyping with sequencing and MassARRAY system among 122 AML patients showed that those with -360CG/-201CT and -360GG/-201TT compound genotypes (n = 41) displayed a favourable response to chemotherapy whereas those with -360CC/-201CC (n = 81) tended to have a poor response (P = 0.025). Moreover, real-time quantitative reverse transcriptase-polymerase chain reaction showed that patients with -360CG/-201CT and -360GG/-201TT genotypes expressed higher level of dCK mRNA compared to those with the -360CC/-201CC genotype (P = 0.0034). Luciferase-reporter assay showed that dCK 5' regulatory region bearing -360G/-201T genotype alone had an eight-fold greater transcriptional activation activity compared to that with -360C/-201C genotype, whereas co-transfection of both -360G/-201T and -360C/-201C constructs mimicked the heterozygous genotype, which exhibited a four-fold greater activity compared to that with -360C/-201C. These results indicate that rSNP haplotypes of dCK gene may serve as a genetic marker for predicting drug responsiveness, which will be beneficial in establishing more effective AML chemotherapeutic regimens.
机译：对1-β-阿拉伯呋喃糖基胞嘧啶（AraC）的耐药性发展是治疗急性髓细胞性白血病（AML）患者的主要障碍。功能性脱氧胞苷激酶（dCK）的缺乏在体外对AraC抵抗中起重要作用。我们筛选了dCK基因的5378 bp序列，包括所有外显子和5'侧翼区域，并在等位基因频率较高的调节区域（rSNPs）中鉴定了两个单核苷酸多态性（SNPs）。这两个rSNP（-201C> T和-360C> G）形成了两个主要的单倍型。测序和MassARRAY系统进行的基因分型对122例AML患者显示，具有-360CG / -201CT和-360GG / -201TT复合基因型（n = 41）的患者对化疗具有良好的反应，而具有-360CC / -201CC（n = 81）的患者）的响应往往较差（P = 0.025）。此外，实时定量逆转录酶-聚合酶链反应显示，与-360CC / -201CC基因型患者相比，-360CG / -201CT和-360GG / -201TT基因型患者表达的dCK mRNA水平更高（P = 0.0034） 。萤光素酶报告基因测定表明，单独带有-360G / -201T基因型的dCK 5'调控区的转录激活活性是与-360C / -201C基因型相比的八倍，而同时共转染-360G / -201T -360C / -201C和-360C / -201C的构建体模仿了杂合基因型，与-360C / -201C相比，它的活性高出四倍。这些结果表明，dCK基因的rSNP单倍型可作为预测药物反应性的遗传标记，这将有助于建立更有效的AML化疗方案。

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