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型激活。这些突变的存在可能会影响对治疗的反应和临床结果。在该 PA R21 资金的支持下，我们在定义 AML 中 FLT3 突变的临床意义方面取得了重大进展。我们建议在即将进行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。 在本研究中，我们将前瞻性评估 FLT3 基因突变（FLT3/ITD 和 FLT3/ALM）、FLT3J 转录水平以及 RTK/R/4S 信号转导通路突变在多机构儿科和儿科患者中的预后意义。成人 AML 试验。我们将进一步确定ITD等位基因比例在FLT3/ITD群体中的作用，并确定13q12杂合性缺失（LOH）在AML发病机制中的意义。我们还将评估 FLT3/ITD 作为微小残留病标记物的效用，以识别复发风险最高的患者。我们将扩展之前在基因表达谱方面的工作，进一步鉴定FLT3突变患者中差异表达的基因，并鉴定和验证参与FLTS突变AML发病机制的基因。这项研究产生的数据将在病程早期识别出具有高复发风险的 AML 患者，并将用于指导未来试验中基于风险的方法的治疗。