MDR Gene Polymorphisms in AML

AML 中的 MDR 基因多态性

• 批准号: 7241067
• 负责人: MARIA R BAER
• 金额: $ 19.26万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-14 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241067
• 关键词: ABCB1 gene; ABCC1 gene; ABCG2 gene; Acute Myelocytic Leukemia; Antineoplastic Agents; Binding; Blast Cell; C10 chemokine; Cancer and Leukemia Group B; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Code; Cyclosporine; DNA; Data; Databases; Drug Efflux; Drug resistance; Enrollment; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genotype; Goals; Gold; Haplotypes; Lead; Malignant Neoplasms; Measurement; Mediating; Mining; Multi-Drug Resistance; Multidrug Resistance Associated Protein 1; Multidrug Resistance Gene; Multidrug Resistance-Associated Proteins; Outcome; P-Glycoprotein; P-Glycoproteins; Patients; Pharmaceutical Preparations; Pharmacotherapy; Proteins; Protocols documentation; Rate; Relapse; Research Design; Resistance; Role; SDZ-PSC-833; Sampling; Single Nucleotide Polymorphism; Stratification; Testing; Tissue Banks; Treatment outcome; Variant; base; chemosensitizing agent; chemotherapy; efflux pump; genetic variant; human ABCG2 protein; improved; insertion/deletion mutation; leukemia; protein expression; response

DESCRIPTION (provided by applicant): The ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp; MDR1; encoded by ABCB1), multidrug resistance-associated protein (MRP-1; encoded by ABCC1) and breast cancer resistance protein (BCRP; encoded by ABCG2) are energy-dependent drug efflux pumps associated with multidrug resistance (MDR) in cell lines and with clinical drug resistance in acute myeloid leukemia (AML). Polymorphisms in the genes encoding these MDR proteins have been identified and have also been associated with treatment outcome. MDR has been a focus of recent Cancer and Leukemia Group B (CALGB) AML clinical trials, including CALGB 9621, 9720 and 19808. Response to chemotherapy has varied widely in the presence and absence of MDR modulation, which is aimed at blocking drug efflux and thus sensitizing AML cells to chemotherapy. In studies designed to explain and predict this variation, pre-treatment AML cells were cryopreserved from patients treated on these protocols for measurement of expression and activity of MDR proteins (CALGB 9760). Pre-treatment blasts were also cryopreserved in the CALGB Leukemia Tissue Bank (CALGB 9665) from all treated patients and are available for MDR genotyping studies (CALGB 20501). These CALGB clinical trials, with outcome data on over 1800 treated patients and cryopreserved pretreatment blast samples, represent a gold mine for further discovery related to the role of MDR proteins in drug response. In the proposed study, we plan to use data and samples collected from these large clinical trials to test the hypothesis that polymorphisms in three MDR genes (ABCB1, ABCC1 and ABCG2) contribute to variation in expression level and activity of MDR proteins, and ultimately to treatment response of AML patients. The overall goal of this discovery-based project is to determine the association of variants in MDR genes with clinical outcome and with expression level and activity of MDR proteins in leukemia samples from AML patients enrolled on these large CALGB clinical trials. In particular, we will associate genetic variants discovered in blast cells with clinical drug response and with MDR protein expression and function in the leukemia cells, as genetic variants in leukemic blast cells may differ from variants in germline DNA because of genetic instability of cancers. The Specific Aims are to: 1. Discover single nucleotide polymorphisms (SNPs) and insertion-deletions in the three MDR genes through re-sequencing in a subset of patient blast samples; 2. Determine the association of common SNPs and haplotypes of the three MDR genes (using tag SNPs identified in Aim 1) with treatment outcome in the clinical studies; and 3. Test the hypothesis that ABCB1, ABCC1 and ABCG2 polymorphisms and haplotypes are associated with Pgp, MRP-1 and BCRP function and expression in pre-treatment blasts from AML patients. The identification of genetic determinants of MDR protein expression and/or function and of AML treatment response will provide important information with potential use in the optimization of AML therapy. Variants in genes that code for multidrug resistance (MDR) proteins have been identified in acute myeloid leukemia (AML) cells and have been implicated in treatment response. Using available outcome data and banked pretreatment AML cells from recent Cancer and Leukemia Group B AML clinical trials, which enrolled over 1800 patients, this project will determine the association of variants in MDR genes with treatment outcome and with expression and activity of MDR proteins in AML cells. The project is expected to provide important information for use in improving AML treatment stratification and outcomes.

描述（由申请人提供）：ATP结合盒（ABC）蛋白P-糖蛋白P-糖蛋白（PGP; MDR1；由ABCB1编码），多药抗性抗性蛋白（MRP-1；由ABCC1；由ABCC1编码）和乳腺癌抗性蛋白（BCRP; ABECRIDEDIDER IS ENTRIDIDERIBE fiment fumperive fecterive fecters fepent feptent feptent; （MDR）在细胞系中和急性髓样白血病（AML）中具有临床耐药性。已经鉴定出编码这些MDR蛋白的基因中的多态性，并且也与治疗结果有关。 MDR一直是最近癌症和白血病B（CALGB）AML临床试验的重点，包括CALGB 9621、9720和19808。在存在和不存在MDR调节的情况下，对化学疗法的反应发生了很大变化，该反应旨在阻断药物外排，从而使AML细胞对化学疗法敏感。在旨在解释和预测这种差异的研究中，预处理AML细胞是从根据这些方案治疗的患者中冷冻保存的，用于测量MDR蛋白的表达和活性（CALGB 9760）。在所有治疗患者的CALGB白血病组织库（CALGB 9665）中，预处理爆炸也被冷冻保存，可用于MDR基因分型研究（CALGB 20501）。这些CALGB临床试验以及有关1800多名治疗患者和冷冻保存预处理样品的结果数据代表了一个金矿，以进一步发现与MDR蛋白在药物反应中的作用有关。在拟议的研究中，我们计划使用从这些大型临床试验中收集的数据和样本来检验以下假设：三个MDR基因（ABCB1，ABCC1和ABCG2）中的多态性有助于MDR蛋白的表达水平和活性变化，并最终导致AML患者治疗反应。这个基于发现的项目的总体目标是确定MDR基因中的变体与临床结局以及来自AML患者的白血病样本中MDR蛋白的表达水平和活性的变体的关联。特别是，我们将将在BLAST细胞中发现的遗传变异与临床药物反应相关联，以及在白血病细胞中的MDR蛋白表达和功能，因为由于癌症的遗传性不稳定，白血病性爆炸细胞中的遗传变异可能与种系DNA中的变异差异。具体目的是：1。发现三个MDR基因中的单核苷酸多态性（SNP）和通过在患者爆炸样品的一部分中进行重新测试而插入。 2。确定三个MDR基因的常见SNP和单倍型的关联（使用AIM 1中鉴定的TAG SNP）与临床研究中的治疗结果的关联； 3。检验假设，即ABCB1，ABCC1和ABCG2多态性和单倍型与AML患者的PGP，MRP-1和BCRP功能以及表达有关。 MDR蛋白表达和/或功能以及AML治疗反应的遗传决定因素的鉴定将在优化AML治疗时提供重要信息。在急性髓样白血病（AML）细胞中已经鉴定出了用于多药耐药性（MDR）蛋白的基因的变体，并与治疗反应有关。使用可用的结果数据并从最近的癌症和白血病组BAML临床试验中纳入了预处理AML细胞，该试验招募了1800多名患者，该项目将确定MDR基因中变体与治疗结果以及AML细胞中MDR蛋白的表达和活性的缔合。预计该项目将提供重要的信息，以改善AML治疗分层和结果。