Novel Biomarkers to Risk-Stratify AML Patients with NPM1^Pos/FLT3-IT^Neg Genotype

对具有 NPM1^Pos/FLT3-IT^Neg 基因型的 AML 患者进行风险分层的新型生物标志物

基本信息

批准号：
9105139
负责人：
DEREK L STIREWALT
金额：
$ 57.62万
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：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105139
关键词：
Accounting Acute Myelocytic Leukemia Address Adult Age Bioinformatics Biological Assay Biological Markers Blast Cell Characteristics Child Classification Clinical Clinical Practice Guideline Complex Coupled Cytogenetics DNA DNA Sequence Data Data Set Development Diagnostic Disease Disease remission Evaluation FLT3 gene Flow Cytometry Future Genes Genome Genomics Genotype Guidelines Hematopoietic Neoplasms Heterogeneity Information Technology Lead Letters Mass Spectrum Analysis Messenger RNA Methods MicroRNAs Modeling Molecular Mutation NPM1 gene Nature Outcome Patients Pediatric Oncology Group Performance Population Probability Prognostic Factor Prognostic Marker Proteins Proteome Proteomics RNA Recommendation Regression Analysis Relapse Research Risk Sampling Southwest Oncology Group Stratification Techniques Technology The Cancer Genome Atlas Transcript Universities Washington base biomedical informatics cost design improved innovation liquid chromatography mass spectrometry molecular marker mutational status new therapeutic target novel novel marker outcome forecast patient population patient stratification prognostic prognostic significance protein biomarkers public health relevance repository response specific biomarkers statistics tool transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies, with NPM1 mutations and FLT3/ITDs being two of the most prognostic biomarkers for this disease. Patients with the NPM1Pos/FLT3-ITDNeg genotype account for approximately 25% of de novo AML cases and are currently classified as better-risk. However, approximately 40% of these patients do not obtain a remission or relapse within 2 years. We hypothesize that AML blasts with the NPM1Pos/FLT3-ITDNeg genotype harbor additional prognostic biomarkers that can be used to more accurately risk-stratify patients with this genotype. Therefore, we will examine viable leukemic blasts from AML patients with this genotype to identify novel genomic, transcriptional and proteomic prognostic biomarkers. We will then develop risk-stratification models incorporating these biomarkers and other prognostic factors and validate these risk-stratification models in an independent population of patients. Specific Aim 1. Identify novel molecular biomarkers associated with prognosis in AML patients with the NPM1Pos/FLT3-ITDNeg genotype. Viable AML blasts will be isolated from patients with intermediate-risk cytogenetics and the NPM1Pos/FLT3-ITDNeg genotype (N=131). Targeted DNA sequencing, global RNA sequencing, and mass spectrometry employing an innovative approach will be used to identify DNA, transcript, and protein biomarkers that are associated with clinical outcomes. Regression analyses, integrating molecular data and other prognostic factors, will be used to identify the most informative biomarkers, and these prognostic biomarkers will be incorporated into risk-stratification models for estimating the probability of overall survival and relapse-free survival. Specific Aim 2. Validate the ability of the biomarkers from Specific Aim 1 to more accurately risk-stratify AML patients with the NPM1Pos/FLT3-ITDNeg genotype. Targeted assays for biomarkers in the risk- stratification models will be developed. The design specifics of these assays will depend upon the characteristics of the target and rely upon previously developed and optimized technology. We will then examine the biomarkers and risk-stratification models in an independent population of AML patients with this genotype (N = 194). The performance of the risk-stratification model(s) employing will be evaluated by estimating AUCs and c-statistics. The results from this proposal will likely lead to the development of improved risk-stratification model(s) for AML patients with the NPM1Pos/FLT3-ITDNeg genotype. In addition, identified biomarkers may have prognostic significance beyond this genotype, and future studies will examine the generalizability of these findings to other AML subpopulations. Furthermore, the comprehensive nature of these studies, spanning from the genome to the proteome, will advance our understanding of the complex interactions among prognostic biomarkers, leading to more informed and potentially directive approaches for future biomarker research.

描述（由申请人提供）：急性髓系白血病 (AML) 是最常见的造血系统恶性肿瘤之一，NPM1 突变和 FLT3/ITD 是具有 NPM1Pos/FLT3-ITDNeg 基因型的患者的两个最具预后性的生物标志物。大约 25% 的新发 AML 病例目前被归类为较高风险，但是，其中大约 40% 的患者并未进行此类筛查。我们追求具有 NPM1Pos/FLT3-ITDNeg 基因型的 AML 母细胞具有额外的预后生物标志物，可用于更准确地对具有该基因型的患者进行风险分层，因此，我们将检查来自该基因型的存活的白血病母细胞。然后，我们将开发结合这些生物标志物和其他预后因素的风险分层模型，并验证这些基因型的 AML 患者。具体目标 1. 从具有中危细胞遗传学和 NPM1Pos 的患者中分离出与具有 NPM1Pos/FLT3-ITDNeg 基因型的 AML 患者预后相关的新型分子生物标志物。 /FLT3-ITDNeg 基因型（N=131）将采用创新方法进行靶向 DNA 测序、全局 RNA 测序和质谱分析来鉴定 DNA，与临床结果相关的转录物和蛋白质生物标志物，整合分子数据和其他预后因素，将用于识别最具信息性的生物标志物，并且这些预后生物标志物将被纳入风险分层模型中，以估计发生概率。总体生存率和具体目标 2. 验证具体目标 1 中的生物标志物对具有 NPM1Pos/FLT3-ITDNeg 基因型的 AML 患者进行更准确风险分层的能力，将开发风险分层模型中生物标志物的靶向检测方法。设计细节为这些测定将取决于目标的特征，并依赖于先前开发和优化的技术，然后我们将检查具有该基因型的独立 AML 患者群体（N = 194）的生物标志物和风险分层模型的表现。采用的风险分层模型将通过估计 AUC 和 c 统计量进行评估。该提案的结果可能会导致针对 AML 患者开发改进的风险分层模型。 NPM1Pos/FLT3-ITDNeg 基因型此外，已确定的生物标志物可能具有超出该基因型的预后意义，未来的研究将检验这些发现对其他 AML 亚群的普遍性。蛋白质组将增进我们对预后生物标志物之间复杂相互作用的理解，为未来的生物标志物研究带来更明智和潜在指导性的方法。