A rapid spontaneous murine model of CN-AML

CN-AML 快速自发小鼠模型

• 批准号: 9174448
• 负责人: H. LEIGHTON GRIMES
• 金额: $ 62.54万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174448
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Algorithms; Alleles; Animal Model; Architecture; Bioinformatics; Biological; Biological Markers; Biological Response Modifier Therapy; Bone Marrow; Catalytic Domain; Cells; Chemotherapy-Oncologic Procedure; Chromosomal translocation; Classification; Complex; Cytogenetics; DNA Modification Methylases; DNMT3a; Data; Data Set; Disease; Epidemiologic Studies; Event; Exons; FLT3 gene; FLT3 inhibitor; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic Markers; Genetically Engineered Mouse; Genomics; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Ligands; MLL-AF9; Malignant Neoplasms; Metamyelocyte; Modeling; Molecular; Molecular Target; Mouse Strains; Mus; Mutation; Myeloproliferative disease; Oncogenes; Oncogenic; Outcome; Pathogenesis; Patients; Pattern; Penetrance; Population; Proteins; Receptor Protein-Tyrosine Kinases; Relapse; Research; Residual Neoplasm; Resistance; Risk; Sampling; Signal Transduction; Somatic Mutation; Spectral Karyotyping; Stat5 protein; Testing; Therapeutic; Validation; Work; bisulfite sequencing; c-myc Genes; chemotherapy; clinically relevant; disorder risk; exome sequencing; fetal liver kinase-2; genome sequencing; in vivo; leukemia; methylome; molecular pathology; mouse model; mutant; novel; novel therapeutic intervention; outcome forecast; programs; response; standard of care; targeted treatment; transcriptome; transcriptome sequencing; treatment response; tumor; whole genome

ABSTRACT Acute myeloid leukemia (AML) is genetically complex, but patients can be divided into those with chromosomal translocations and those that are cytogenetically normal (CN-AML). CN-AML represents nearly 50% of human AML cases, and the overall 5-year survival for adults with CN-AML is approximately 30%. Mutations in the de novo DNA methyltransferase DNMT3A and internal tandem duplications of the FMS-like tyrosine kinase 3 (FLT3-ITD) and are two of the most frequent events in CN-AML. Moreover, recent whole-genome sequencing of CN-AML patient samples identified: 1) high-frequency co-occurrence of FLT3 and DNMT3A mutations, and 2) corresponding changes to the risk classification for these CN-AML patients to a poorer prognosis. Because human epidemiologic studies cannot easily control for factors that confer disease risk, genetically engineered mouse (GEM) strains provide essential tractable platforms to mechanistically dissect disease pathobiology, heterogeneity and therapeutic response. Although neither Flt3-ITD nor inducible deletion of Dnmt3a induces spontaneous leukemia in mice, when we combined Flt3-ITD mutant alleles with inducible deletion of Dnmt3a we find a spontaneous, rapidly lethal, completely-penetrant, and transplantable AML. We hypothesize that inducible deletion of Dnmt3a in Flt3-ITD mice produces a faithful model of human CN-AML that can be used to infer essential biological and molecular factors that constitute therapeutic response. To this end, we propose, genomic, cytogenetic, and single-cell molecular analyses (with comparison to primary human CN-AML) to deconvolute both the tumor architecture and the underlying cellular states. We expect the proposed research to deliver a validated murine model of FLT3-ITD/DNMT3a-mutant CN-AML with defined translational utility.

抽象的 急性髓系白血病 (AML) 基因复杂，但患者可分为染色体异常患者 易位和细胞遗传学正常的易位（CN-AML）。 CN-AML 占人类近 50% AML 病例，成人 CN-AML 的总体 5 年生存率约为 30%。德的突变 novo DNA 甲基转移酶 DNMT3A 和 FMS 样酪氨酸激酶 3 的内部串联重复 (FLT3-ITD) 和 是 CN-AML 中最常见的两个事件。此外，最近的全基因组测序 确定的 CN-AML 患者样本：1) FLT3 和 DNMT3A 突变高频同时出现，以及 2）这些CN-AML患者的风险分类相应改变，预后较差。因为 人类流行病学研究无法轻易控制导致疾病风险的因素，基因工程 小鼠（GEM）品系提供了必要的易处理平台来机械地剖析疾病病理学， 异质性和治疗反应。尽管 Flt3-ITD 和 Dnmt3a 的诱导型缺失均不会诱导 当我们将 Flt3-ITD 突变等位基因与 Dnmt3a 的诱导缺失相结合时，小鼠自发性白血病 我们发现了一种自发的、快速致死的、完全渗透的、可移植的 AML。我们假设 Flt3-ITD 小鼠中 Dnmt3a 的诱导缺失产生了可靠的人类 CN-AML 模型，可用于 推断构成治疗反应的重要生物和分子因素。为此，我们建议， 基因组、细胞遗传学和单细胞分子分析（与原发性人类 CN-AML 比较） 对肿瘤结构和潜在的细胞状态进行解卷积。我们期望拟议的研究 提供经过验证的 FLT3-ITD/DNMT3a 突变 CN-AML 小鼠模型，具有明确的转化效用。