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(申请人提供)：ATP结合盒(ABC)蛋白P-糖蛋白(PGP；MDR1，由ABCB1编码)、多药耐药相关蛋白(MRP-1，由ABCC1编码)和乳腺癌耐药蛋白(BCRP，由ABCG2编码)是与细胞系多药耐药(MDR)相关的能量依赖性药物外排泵，与急性髓系白血病(AML)的临床耐药有关。编码这些多药耐药蛋白的基因的多态性已经被发现，并且也与治疗结果有关。MDR已成为最近癌症和白血病B组(CALGB)急性髓系白血病临床试验的焦点，包括CALGB9621、9720和19808。在有无MDR调节的情况下，对化疗的反应差别很大，MDR调节的目的是阻止药物外流，从而使AML细胞对化疗敏感。在旨在解释和预测这种变异的研究中，对按这些方案治疗的患者的治疗前AML细胞进行冷冻保存，以测量MDR蛋白的表达和活性(CALGB 9760)。治疗前的原始细胞也被冷冻保存在CALGB白血病组织库(CALGB 9665)中，可用于多药耐药基因分型研究(CALGB 20501)。这些CALGB临床试验包含了1800多名接受治疗的患者和冷冻保存的预处理BLAST样本的结果数据，为进一步发现MDR蛋白在药物反应中的作用提供了一座金矿。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这一假设，即三个MDR基因(ABCB1、ABCC1和ABCG2)的多态有助于MDR蛋白表达水平和活性的变化，并最终影响AML患者的治疗反应。这个以发现为基础的项目的总体目标是确定MDR基因变异与临床结果以及参加这些大型CALGB临床试验的AML患者的白血病样本中MDR蛋白的表达水平和活性之间的关联。特别是，我们将把在原始细胞中发现的遗传变异与临床药物反应以及白血病细胞中多药耐药蛋白的表达和功能联系起来，因为由于癌症的遗传不稳定性，白血病原始细胞中的遗传变异可能不同于胚系DNA中的变异。其具体目的是：1.通过对患者BLAST样本的重新测序，发现三个MDR基因中的单核苷酸多态(SNPs)和插入-缺失；2.在临床研究中确定常见的SNPs和三个MDR基因的单倍型(使用Aim 1中确定的标签SNPs)与治疗结果的相关性；以及3.验证ABCB1、ABCC1和ABCG2多态和单倍型与PGP、MRP-1和BCRP功能和表达相关的假设。确定MDR蛋白表达和/或功能以及AML治疗反应的遗传决定因素将为AML治疗的优化提供重要信息，具有潜在的应用价值。编码多药耐药(MDR)蛋白的基因变异在急性髓系白血病(AML)细胞中被发现，并与治疗反应有关。利用现有的结果数据和最近的癌症和白血病B组急性髓细胞白血病临床试验中储存的预处理AML细胞，该项目将确定MDR基因变异与治疗结果以及AML细胞中多药耐药蛋白的表达和活性的关系。预计该项目将提供重要的信息，用于改善AML的治疗分层和结果。