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: 9899941
• 负责人: DEREK L STIREWALT
• 金额: $ 46.78万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899941
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Age; Biological Assay; Biological Markers; Characteristics; Child; Classification; Clinical; Complex; Coupled; Cryopreservation; Cytogenetics; DNA; DNA sequencing; Data; Data Set; Development; Diagnostic; Disease; Disease remission; Evaluation; FLT3 gene; Flow Cytometry; Future; Genes; Genetic Transcription; Genome; Genomics; Genotype; Guidelines; Hematopoietic Neoplasms; Heterogeneity; Information Technology; Laboratories; 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; Risk stratification; Sampling; Southwest Oncology Group; Techniques; Technology; The Cancer Genome Atlas; Transcript; Universities; Washington; base; bioinformatics pipeline; bioinformatics tool; biomedical informatics; clinical practice; cost; design; improved; innovation; leukemia; 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; synergism; transcriptome; transcriptome sequencing; treatment guidelines

 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 是该疾病的两个最具预后性的生物标志物。具有 NPM1Pos/FLT3-ITDNeg 基因型的患者约占新发 AML 病例的 25%，目前被归类为较高风险。然而，大约 40% 的患者在 2 年内没有获得缓解或复发。我们假设具有 NPM1Pos/FLT3-ITDNeg 基因型的 AML 母细胞含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，我们将检查具有该基因型的 AML 患者的活白血病母细胞，以确定新的基因组、转录和蛋白质组预后生物标志物。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，并在独立的患者群体中验证这些风险分层模型。具体目标 1. 鉴定与 NPM1Pos/FLT3-ITDNeg 基因型 AML 患者预后相关的新型分子生物标志物。将从具有中等风险细胞遗传学和 NPM1Pos/FLT3-ITDNeg 基因型 (N=131) 的患者中分离出存活的 AML 母细胞。采用创新方法的靶向 DNA 测序、全局 RNA 测序和质谱分析将用于识别与临床结果相关的 DNA、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的回归分析将用于识别信息最丰富的生物标志物，这些预后生物标志物将被纳入风险分层模型中，以估计总体生存的概率和 无复发生存。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。将通过估计 AUC 和 c 统计量来评估所采用的风险分层模型的性能。 该提案的结果可能会导致针对 NPM1Pos/FLT3-ITDNeg 基因型的 AML 患者开发改进的风险分层模型。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。此外，这些研究的综合性，从基因组到蛋白质组，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。