Next-Generation Sequencing of Therapy-Related Acute Myeloid Leukemia

治疗相关急性髓系白血病的下一代测序

• 批准号: 7915136
• 负责人: Megan McNerney
• 金额: $ 3.58万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915136
• 关键词: Acute; Adverse effects; Alkylating Agents; Biological Markers; Cancer Survivor; Cells; Chicago; Clinical; Complication; Disease; Disease remission; Dysmyelopoietic Syndromes; Gene Fusion; Gene Mutation; Genome; Goals; Hematopoietic; Human; In Vitro; Incidence; Lesion; Messenger RNA; Molecular; Molecular Abnormality; Mutate; Mutation; Myelogenous; Nature; Outcome; Pathway interactions; Patients; Proteins; Radiation; Refractory; Sampling; Techniques; Technology; Testing; Therapeutic; Therapy-Related Acute Myeloid Leukemia; Topoisomerase-II Inhibitor; Universities; Validation; cancer cell; chemotherapy; design; effective therapy; gene therapy; leukemia; leukemogenesis; next generation; outcome forecast; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Therapy-related acute myeloid eukemia/myelodysplastic syndrome (t-AML) is a complication that occurs in up to 10% of patients receiving chemotherapy with alkylating agents, topoisomerase II inhibitors, or radiation. This disease has increased in incidence as patients achieve longer remissions. T-AML remains refractory to current therapy and carries a uniformly fatal prognosis, with a median survival of 8-10 months. In this proposal, it is hypothesized that transformed hematopoietic cells have genetic mutations that drive leukemogenesis and can serve as therapeutic targets and biomarkers of disease. The specific aims are designed to test this hypothesis by sequencing the leukemic mRNA of t-AML patients using next-generation technology to identify genetic abnormalities, including potential gene fusions and mutations. Specific Aim 1 is the discovery and prioritization of molecular lesions in t-AML leukemia samples by sequencing all mRNAs in t- AML human samples. Specific Aim 2 is the validation of mutations by molecular techniques using the large number of t-AML samples available to us at the University of Chicago. Specific Aim 3 is to study the functional significance of mutations in vitro using a multitude of approaches dictated by the nature of the mutated gene products discovered. This information will allow the identification of pathways altered in t-AML, correlate these aberrations with clinical outcome, identify potential biomarkers, and generate candidate targets for leukemia therapeutics. PUBLIC HEALTH RELEVANCE: Therapy-related acute myeloid leukemia (t-AML) is a side-effect of chemotherapy that occurs in up to 10% of cancer survivors and does not have an effective treatment. Cutting-edge sequencing technology will be used to analyze the genome of t-AML cancer cells in this project. The goal of this proposal is to understand the genetics of t-AML and identify the cause and a treatment for this disease.

描述（由申请方提供）：治疗相关急性骨髓性白血病/骨髓增生异常综合征（t-AML）是一种并发症，在接受烷化剂、拓扑异构酶II抑制剂或放疗化疗的患者中发生率高达10%。随着患者缓解时间的延长，这种疾病的发病率增加。T-AML对目前的治疗仍然是难治性的，并且具有一致的致命预后，中位生存期为8-10个月。在该提案中，假设转化的造血细胞具有驱动白血病发生的基因突变，并且可以作为疾病的治疗靶点和生物标志物。具体目标旨在通过使用下一代技术对t-AML患者的白血病mRNA进行测序来验证这一假设，以识别遗传异常，包括潜在的基因融合和突变。具体目标1是通过对t-AML人类样品中的所有mRNA进行测序来发现t-AML白血病样品中的分子病变并对其进行优先排序。具体目标2是使用芝加哥大学提供的大量t-AML样本，通过分子技术验证突变。具体目标3是使用由所发现的突变基因产物的性质决定的多种方法在体外研究突变的功能意义。这些信息将允许识别t-AML中改变的途径，将这些畸变与临床结果相关联，识别潜在的生物标志物，并产生白血病治疗的候选靶点。 公共卫生关系：治疗相关性急性髓性白血病（t-AML）是化疗的副作用，发生在高达10%的癌症幸存者中，并且没有有效的治疗方法。尖端测序技术将用于分析t-AML癌细胞的基因组。该提案的目标是了解t-AML的遗传学，并确定这种疾病的病因和治疗方法。