Biology and Prognostic implications of Flt3 mutations in AML

Flt3 突变对 AML 的生物学和预后影响

基本信息

批准号：
7910337
负责人：
SOHEIL MESHINCHI
金额：
$ 17.12万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7910337
关键词：
13q12 Acute Myelocytic Leukemia Adult Adult Acute Myeloblastic Leukemia Biology Blast Cell Cell Proliferation Chemotherapy-Oncologic Procedure Childhood Children&apos s Oncology Group Clinical Cytogenetics Data Demographic Aging Dimerization Disease Disease Resistance Disease remission Disease-Free Survival Evaluation FLT3 gene Funding Future Gene Expression Profiling Genes Genetic Individual Laboratories Lead Link Long-Term Survivors Loss of Heterozygosity Marrow Methods Molecular Biology Molecular Profiling Multi-Institutional Clinical Trial Mutation Outcome Pathogenesis Pathway interactions Patients Platelet-Derived Growth Factor Point Mutation Population Prognostic Factor Prospective Studies Receptor Activation Receptor Gene Receptor Protein-Tyrosine Kinases Receptor Tyrosine Kinase Gene Relapse Remission Induction Research Personnel Residual Neoplasm Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Signal Transduction Signal Transduction Pathway Somatic Mutation Southwest Oncology Group Stem cell transplant Subgroup Testing Transcript Work aggressive therapy base chemotherapy clinically significant cohort effective therapy high risk improved insight mutant novel prognostic programs response

项目摘要

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，并引起FLT3受体酪氨酸激酶的本构激活。这些突变的存在可能会影响对治疗和临床结果的反应。在支持此PA的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步骤。我们建议进一步描述FLT3突变在即将到来的小儿和成人多机构试验中的生物学和临床意义，并在高风险的复发中更全面地定义了人群。在这项研究中，我们将前瞻性评估FLT3基因（FLT3/ITD和FLT3/ALM）突变的预后意义，FLT3J转录物水平以及RTK/R/R/4S信号转导途径的突变在多生育的儿科和成人AML试验中。我们将进一步确定ITD等位基因比率在FLT3/ITD群体中的作用，并确定杂合性丧失（LOH）的显着性（13q12 in，in AML的发病机理）。我们还将评估FLT3/ITD作为最小残留疾病的标记的效用，以鉴定出最高的复发风险。我们将扩展我们先前关于基因表达分析的工作，以进一步鉴定在FLT3突变患者中差异表达的基因，并鉴定和验证与FLTS突变AML发病机理有关的基因。这项研究产生的数据将在其疾病早期识别出高风险复发的AML患者，并将用于在以后的试验中指导基于风险的方法中的治疗。