Biology/prognostic implications of Flt3 mutations in AML

Flt3 突变对 AML 的生物学/预后影响

• 批准号: 6911155
• 负责人: SOHEIL MESHINCHI
• 金额: $ 40.42万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911155
• 关键词: acute myelogenous leukemia; clinical research; gene expression profiling; gene mutation; genetic markers; genetic susceptibility; human genetic material tag; human tissue; loss of heterozygosity; microarray technology; minimal residual disease; molecular oncology; neoplasm /cancer genetics; patient oriented research; prognosis; protein tyrosine kinase

DESCRIPTION (provided by applicant): Activating mutations of the FLT3 receptor gene are the most common somatic mutations in AML and cause constitutive activation of the FLT3 receptor tyrosine kinase. Presence of these mutations may impact response to therapy and clinical outcome. With support of R21 funding from this PA we have made significant strides in defining the clinical significance of FLT3 mutations in AML. We propose to further delineate the biology and clinical significance of the FLT3 mutations in the upcoming pediatric and adult multi-institutional trials and more fully define a population at high-risk of relapse. In this study we will prospectively evaluate the prognostic significance of mutations of the FLT3 gene (FLT3/ITD and FLT3/ALM), FLT3J transcript levels, as well as mutations of the RTK/R/4S signal transduction pathway in multi-institutional pediatric and adult AML trials. We will further establish the role of ITD allelic ratio in FLT3/ITD population and determine the significance of the loss of heterozygosity (LOH) of 13q12 in, the pathogenesis of AML. We will also evaluate the utility of FLT3/ITD as a marker for minimal residual disease to identify patients at the highest risk of relapse. We will expand on our previous work on gene expression profiling to further identify genes that are differentially expressed in patients with FLT3 mutations and identify and validate genes involved in the pathogenesis of FLTS-mutant AML. The data generated from this study will identify AML patients at high-risk of relapse early in the course of their disease, and will be used to guide therapy in risk-based approach in future trials.

描述（由申请人提供）：FLT3受体基因的激活突变是AML中最常见的体细胞突变，并导致FLT3受体酪氨酸激酶的组成性激活。这些突变的存在可能影响对治疗的反应和临床结果。在该项目R21资金的支持下，我们在确定AML中FLT3突变的临床意义方面取得了重大进展。我们建议在即将到来的儿科和成人多机构试验中进一步描述FLT3突变的生物学和临床意义，并更全面地定义复发高风险人群。