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

• 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
• 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

 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（由适用提供）：急性髓细胞性白血病（AML）是最常见的造血恶性肿瘤之一，NPM1突变和FLT3/ITD是这种疾病的两个最终预后的生物标志物。 NPM1POS/FLT3-ITDNEG基因型的患者约占NOVO AML病例的25％，目前被归类为更好的风险。但是，这些患者中约有40％在2年内未能缓解或继电器。我们假设AML使用NPM1POS/FLT3-ITDNEG基因型具有额外的预后生物标志物，可用于更准确地使用该基因型风险分层。因此，我们将检查具有该基因型的AML患者的可行白血病爆炸，以鉴定新的基因组，转录和蛋白质组学预后生物标志物。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，并在独立的患者人群中验证这些风险分层模型。具体目的1。鉴定NPM1POS/FLT3-ITDNEG基因型的AML患者的预后相关的新型分子生物标志物。将从中等风险的细胞遗传学和NPM1POS/FLT3-ITDNEG基因型（n = 131）中分离出可行的AML爆炸。采用创新方法的靶向DNA测序，全局RNA测序和质谱法将用于识别与临床结果相关的DNA，转录和蛋白质生物标志物。回归分析，整合分子数据和其他预后因素，将用于识别最有用的生物标志物，这些预后的生物标志物将被纳入风险分解模型中，以估计整体生存和总体生存的可能性 无复发生存。特定目标2。验证生物标志物从特定目标1更准确地划分为NPM1POS/FLT3-ITDNEG基因型的AML患者的能力。将开发出风险分层模型中生物标志物的有针对性测定。设计细节 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AML患者的独立人群中的生物标志物和风险分层模型（n = 194）。采用风险分层模型的性能将通过估计AUC和C统计数据来评估。该提案的结果可能会导致NPM1POS/FLT3-ITDNEG基因型的AML患者改善风险分层模型的发展。此外，鉴定的生物标志物可能具有超出该基因型的预后意义，未来的研究将研究这些发现对其他AML亚群的普遍性。此外，这些研究的全面性质从基因组到蛋白质组，将促进我们对预后生物标志物之间复杂相互作用的理解，从而为未来的生物标志物研究提供了更加知情的和潜在的指令方法。