Next-Generation Sequencing of Therapy-Related Acute Myeloid Leukemia

描述(申请人提供)：与治疗相关的急性髓系白血病/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抑制剂或放射治疗的患者中高达10%。随着患者病情得到更长时间的缓解，这种疾病的发病率也有所增加。T-AML对目前的治疗方法仍然难以奏效，预后均为致命，中位生存期为8-10个月。在这项提议中，假设转化的造血细胞具有驱动白血病发生的基因突变，并可作为治疗靶点和疾病的生物标志物。具体目的是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人类样本中的所有mRNAs进行测序，发现t-AML白血病样本中的分子病变并确定其优先顺序。具体目标2是利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是利用已发现的突变基因产物的性质所规定的多种方法，在体外研究突变的功能意义。这些信息将允许识别t-AML中改变的通路，将这些异常与临床结果相关联，识别潜在的生物标记物，并产生白血病治疗的候选靶点。 公共卫生相关性：与治疗相关的急性髓系白血病(t-AML)是化疗的副作用，发生在多达10%的癌症幸存者身上，并且没有有效的治疗方法。在这个项目中，将使用尖端测序技术来分析t-AML癌细胞的基因组。这项建议的目标是了解t-AML的遗传学，并确定这种疾病的病因和治疗方法。

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.