Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia
Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia
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DOI：
10.2217/pgs.11.149
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发表时间：
2012-02-01
期刊：
影响因子：
2.1
通讯作者：
Balasubramanian, Poonkuzhali
中科院分区：
文献类型：
--
作者：
Abraham, Ajay;Varatharajan, Savitha;Balasubramanian, Poonkuzhali
目的：胞苷脱氨酶（CDA）不可逆地使阿糖胞苷（Ara-C）脱氨基，阿糖胞苷是急性髓细胞白血病（AML）诱导和巩固治疗的关键组分。CDA过表达导致Ara-C耐药性，而表达降低则与毒性相关。我们评估了成人AML患者和正常对照中CDA mRNA表达变化的影响因素，以及它们如何导致AML细胞中Ara-C的细胞毒性。材料和方法：采用定量逆转录聚合酶链反应（RT-PCR）检测100例初治AML患者和36例正常对照者CDAmRNA的表达。通过直接测序筛选CDA基因中的遗传变体。Ara-C的IC 50通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑测定法测定。结果：AML患者和正常对照组中CDA RNA表达和Ara-C IC 50存在较大差异。共鉴定出14个序列变异体，其中3个（-33delC、内含子2 TCAT重复和3 '非翻译区816 delC变异体）与RNA表达显著相关，非同义编码变异体79 A>C与Ara-C细胞毒性相关。结论：CDA基因变异解释了RNA表达的变化，并可能成为个体化阿糖胞苷治疗的候选者。
Aim: Cytidine deaminase (CDA) irreversibly deaminates cytarabine (Ara-C), a key component of acute myeloid leukemia (AML) induction and consolidation therapy. CDA overexpression results in Ara-C resistance, while decreased expression is associated with toxicity. We evaluated factors influencing variation in CDA mRNA expression in adult AML patients and normal controls, and how they contributed to Ara-C cytotoxicity in AML cells. Materials & methods: CDA mRNA expression in 100 de novo AML patients and 36 normal controls were determined using quantitative reverse-transcriptase PCR. Genetic variants in the CDA gene were screened by direct sequencing. IC50 of Ara-C was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: CDA RNA expression as well as Ara-C IC50 showed wide variation in AML samples and normal controls. Fourteen sequence variants were identified, three of which (-33delC, intron 2 TCAT repeat and the 3'untranslated region 816delC variants) showed significant association with RNA expression and the nonsynonymous coding variant 79A>C was associated with Ara-C cytotoxicity. Conclusion: CDA genetic variants explain the variation in RNA expression and may be candidates for individualizing Ara-C therapy.