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（由申请人证明）：急性髓样白血病（AML）是最常见的造血性恶性肿瘤之一，NPM1 MUTAT3/ ITD是目前大约25％的AML的预后生物标志物之一。但是，这些患者中约有40％在2年内没有缓解或复发。使用这种基因组，转录和蛋白质组学的生物标志物会发展出生物标志物和其他预后因素的风险分层模型。 NPM1POS/FLT3-ITDNE G基因型的AML患者将从互联网和NPM1POS/FLT3-ITDNEG基因型中分离出可行的AML爆炸（n = 131）。确定与临床结果相关的DNA，转录本和蛋白质生物标志物。 没有复发的生存目标。设计细节 这些测定将取决于目标，并依靠E型AML患者的独立性（n = 194）与Lear Learl一样，该提案的结果是E AML的NPM1POS/FLT3-ITDNEG基因型的改进的风险分层模型的开发。其他亚种。