Biology and Prognostic implications of Flt3 mutations in AML

描述(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，会导致Flt3受体酪氨酸激酶的结构性激活。这些突变的存在可能会影响治疗反应和临床结果。在该协会R21基金的支持下，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，并更充分地定义复发高危人群。 在这项研究中，我们将在多机构的儿童和成人AML试验中前瞻性地评估Flt3基因突变(Flt3/ITD和Flt3/ALM)、Flt3J转录本水平以及RTK/R/4S信号转导通路的突变对预后的意义。我们将进一步确定ITD等位基因比例在Flt3/ITD人群中的作用，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作为微小残留病标志物的实用性，以确定具有最高复发风险的患者。我们将在以前基因表达谱工作的基础上，进一步识别在Flt3突变患者中差异表达的基因，并识别和验证参与Flts突变AML发病机制的基因。这项研究产生的数据将在他们病程的早期识别AML患者复发的高风险，并将在未来的试验中用于指导基于风险的方法的治疗。

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.