Biology/prognostic implications of Flt3 mutations in AML

描述（由申请方提供）：FLT 3受体基因的激活突变是AML中最常见的体细胞突变，并导致FLT 3受体酪氨酸激酶的组成性激活。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的R21资金支持下，我们在确定AML中FLT 3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FLT 3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FLT 3基因突变（FLT 3/ITD和FLT 3/ALM）、FLT 3 J转录水平以及RTK/R/4S信号转导通路突变在多机构儿科和成人AML试验中的预后意义。我们将进一步确定ITD等位基因比例在FLT 3/ITD人群中的作用，并确定13 q12杂合性缺失（洛）在AML发病机制中的意义。我们还将评估FLT 3/ITD作为微小残留病标志物的效用，以确定复发风险最高的患者。我们将扩展我们以前的基因表达谱的工作，以进一步确定在FLT 3突变患者中差异表达的基因，并确定和验证参与FLTS突变型AML发病机制的基因。本研究产生的数据将在疾病早期识别出具有复发高风险的AML患者，并将用于指导未来试验中基于风险的治疗方法。

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.