Towards an inclusive genomic risk classification for acute myeloid leukemia (AML)

迈向急性髓系白血病 (AML) 的包容性基因组风险分类

• 批准号: 10752188
• 负责人: Ann-Kathrin Eisfeld
• 金额: $ 68.74万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752188
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; African ancestry; Algorithms; American; Architecture; Archives; Assessment tool; Biological; Biological Assay; Biological Testing; Biology; Cell surface; Cells; Classification; Clinical; Clinical Pathways; Clonality; Cytogenetics; DNA Resequencing; Data; Disease; European; European ancestry; Exhibits; FLT3 gene; Frequencies; Gene Mutation; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomics; Genotype; Goals; Human; Human Genetics; Incidence; Knowledge; Malignant Neoplasms; Medical Genetics; Modality; Modeling; Molecular; Mutate; Mutation; Oncogenic; Open Reading Frames; Outcome; Patients; Population; Prediction of Response to Therapy; Prognosis; Prognostic Marker; Publications; Publishing; RNA Splicing; RNA analysis; Recurrence; Relapse; Residual Neoplasm; Resistance; Risk; Risk Adjustment; Role; Sampling; Somatic Mutation; Testing; Therapeutic; Variant; XCL1 gene; Xenograft Model; Xenograft procedure; acute myeloid leukemia cell; cancer genetics; chemotherapy; clinical practice; clinical risk; cohort; driver mutation; drug development; exome; exome sequencing; genetic panel test; genetic risk assessment; in vivo; in vivo evaluation; leukemia; leukemic stem cell; leukemogenesis; multimodality; multiple omics; mutant; novel; precision oncology; prognostic; prognostic significance; response; risk stratification; therapy development; tool; transcriptome sequencing; treatment response; treatment stratification; tumor progression

A. PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common adult acute leukemia. Molecular features such as cytogenetics and somatic mutations are essential components of risk stratification; used in daily clinical practice to determine treatment modality and intensity. Our knowledge of recurrent genetic AML-associated features, survival associations, subsequent genetic risk classification and clinical practice is informed by large- scale genomic studies performed over the past decade on patients of Central-European ancestry. Thus, current clinical practice is predicated on the supposition that adequate testing has been performed, and that genetic background should not affect the known AML-associated genetic and genomic landscape and genes that associate with treatment response and/or that drive AML-genesis. However, our published and preliminary data reveal that ancestry affects not only the frequencies and impact of known AML-associated gene mutations, but also multiple recurrent variants in genes thus-far not implicated in AML-genesis. We hypothesize that: a) known AML-associated drivers may carry different prognostic significance and might need to be adjusted in clinical risk classifications depending on ancestry, and b) some unrecognized molecular features are ancestry-associated drivers of AML-genesis and/or therapy resistance. We propose to extend our initial studies of AML genomes and genomics to provide statistical confidence around frequently mutated genes, and a more inclusive molecularly-adjusted risk and treatment stratification for AML patients. Next, we will focus on NPM1c, a genotype which confers favorable outcome in AML patients with Central-European ancestry, but poor outcomes in other ancestries. We will use cutting-edge single-cell multiomic assays to delineate bystander clonal mutations from potential driver mutations, then we will biologically test their role in clonality/leukemia-stem-cell frequency and treatment response. We expect to provide an inclusive characterization of the genetic and genomic landscape of AML, identify those variants with prognostic significance, and provide exemplars of here-to-fore unrecognized drivers of treatment response and survival. The overall goal is to enable precision oncology approaches which accommodate the effects of underlying human genetics.

A. 项目概要 急性髓系白血病（AML）是最常见的成人急性白血病。分子特征如 细胞遗传学和体细胞突变是风险分层的重要组成部分；用于日常临床 练习以确定治疗方式和强度。我们对复发性遗传性 AML 相关知识的了解 特征、生存关联、随后的遗传风险分类和临床实践均由大量信息提供信息 过去十年对中欧血统患者进行的大规模基因组研究。因此， 当前的临床实践是基于已经进行了充分测试的假设，并且 遗传背景不应影响已知的 AML 相关遗传和基因组景观和基因 与治疗反应相关和/或驱动 AML 发生。然而，我们已发布的和初步的 数据显示，血统不仅影响已知 AML 相关基因的频率和影响 突变，而且还包括迄今为止与 AML 发生无关的基因中的多个反复出现的变异。我们 假设：a) 已知的 AML 相关驱动因素可能具有不同的预后意义，并且可能需要 根据血统对临床风险分类进行调整，以及 b) 一些未被识别的分子 这些特征是 AML 发生和/或治疗耐药的与祖先相关的驱动因素。我们建议延长我们的 AML 基因组和基因组学的初步研究，为频繁突变提供统计可信度 基因，以及针对 AML 患者的更具包容性的分子调整风险和治疗分层。接下来，我们 将重点关注 NPM1c，这是一种为中欧 AML 患者带来良好结果的基因型 血统，但其他血统的结果很差。我们将使用尖端的单细胞多组学分析来 将旁观者克隆突变与潜在驱动突变区分开来，然后我们将从生物学上测试它们在 克隆性/白血病干细胞频率和治疗反应。我们期望提供一个包容性的 描述 AML 的遗传和基因组景观，识别具有预后意义的变异 意义，并提供迄今为止尚未认识到的治疗反应和生存驱动因素的范例。 总体目标是实现精准肿瘤学方法，适应潜在的影响 人类遗传学。