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(Flt3内部串联重复、Fit3/ITD和Flt3点突变，Fit3/PM)的存在可能导致较低的缓解率和较高的复发率。本项目的目的是评估接受国家多机构试验(CCG、POG和SWOG)治疗的儿童和成人AML患者的诊断骨髓标本中的Flt3激活突变，并将Flt3突变与其他生物标志物相关联。最初，将确定是否存在Flt3激活突变，并将其与临床特征和结果相关联，以试图定义这些突变的预后意义。Fit3/ITD突变的临床意义将进一步通过测定13号染色体的ITD等位基因比率和杂合性缺失(LOH)来表征。我们与儿科和成人同事建立了一个合作网络，在这个网络中，关于Flt3激活突变的信息将被合并，并与c-kit激活突变、最小残留疾病和RNA表达谱的数据相关联，以便更好地定义这种突变的生物学。我们还将以前瞻性的方式进行FLT3突变分析，作为国家第三阶段成人AML试验(SWOG SO106)和儿科试验(COG AML试验-正在开发中)的一部分，以确定治疗强化是否会改变Flt3突变的预后意义。该赠款项目将对迄今为止测试过的最大患者群体中的Flt3突变进行广泛的评估，并将数据与其他生物标记相关联。

DESCRIPTION (provided by applicant): Activating mutations in the Flt3 receptor gene are the most common somatic mutation in AML and cause constitutive activation of the Flt3 receptor tyrosine kinase. Presence of these mutations (Flt3 internal tandem duplication, FIt3/ITD and Flt3 point mutations, FIt3/PM) may lead to lower rate of remission induction and increased rate of relapse. The aim of this project is to evaluate diagnostic marrow specimens from pediatric and adult AML patients treated on national multi-institutional trials (CCG, POG and SWOG) for Flt3 activating mutations and to correlate FLT3 mutations with other biologic markers. Initially, presence of Flt3 activating mutations will be determined and correlated with clinical characteristics and outcome in an attempt to define the prognostic significance of these mutations. Clinical significance of the FIt3/ITD mutations will further be characterized by determination of the ITD allelic ratio and Loss of Heterozygosity (LOH) of Chromosome 13. We have created a collaborative network with our pediatric and adult colleagues where the information generated on Flt3 activating mutations will be merged and correlated with the data on c-kit activating mutations, minimal residual disease and RNA expression profile in order to better define the biology of this mutation. We will also perform Flt3 mutational analysis as a part of national phase III AML trials in Adults (SWOG SO106) and pediatrics (COG AML trial- under development) in a prospective fashion to determine whether therapy intensification would alter the prognostic significance of Flt3 mutations. This grant project will undertake an extensive evaluation of Flt3 mutations in the largest patient population tested to date and will correlate the data with other biologic markers.