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 急性髓样白血病（AML）在遗传上很复杂，但患者可以分为患有染色体的患者 易位和细胞遗传学正常的易位（CN-AML）。 CN-AML代表人类的近50％ AML病例，CN-AML成年人的总体5年生存率约为30％。 DE中的突变 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），是CN-AML中最常见的两个事件。而且，最近的全基因组测序 确定的CN-AML患者样本：1）FLT3和DNMT3A突变的高频共发生，以及 2）对这些CN-AML患者的风险分类的相应变化为较差的预后。因为 人流行病学研究无法轻易控制赋予疾病风险的因素，基因工程 小鼠（GEM）菌株为机械学剖析病理生物学的必不可少的平台， 异质性和治疗反应。尽管DNMT3A的FLT3-ITD和诱导删除均未引起 当我们将FLT3-ITD突变等位基因与DNMT3A的诱导缺失相结合时，小鼠的自发白血病 我们发现一种自发的，迅速致命的，完全渗透的和可移植的AML。我们假设这一点 在FLT3-ITD小鼠中DNMT3A的诱导删除产生人类CN-AML的忠实模型，可用于 推断构成治疗反应的基本生物学和分子因子。为此，我们建议， 基因组，细胞遗传学和单细胞分子分析（与原代人CN-AML相比）与 肿瘤结构和下层细胞状态都卷染色。我们期望拟议的研究 提供具有定义转化实用程序的flt3-itd/dnmt3a突变的CN-AML的经过验证的鼠模型。