A rapid spontaneous murine model of CN-AML

摘要 急性髓细胞白血病（AML）是一种遗传复杂的疾病，但患者可以分为染色体异常的患者。 易位和细胞遗传学正常的那些（CN-AML）。CN-AML占人类AML的近50%。 AML病例中，CN-AML成人的总体5年生存率约为30%。突变在DE 新DNA甲基转移酶DNMT 3A和FMS样酪氨酸激酶3的内部串联重复 （FLT 3-ITD），是CN-AML中最常见的两种事件。此外，最近的全基因组测序 鉴定的CN-AML患者样本中：1）FLT 3和DNMT 3A突变的高频率共现，以及 2)这些CN-AML患者的风险分类发生相应变化，预后较差。因为 人类流行病学研究不能轻易地控制赋予疾病风险的因素，基因工程 小鼠（GEM）品系提供了基本的易处理的平台来机械地剖析疾病病理学， 异质性和治疗反应。尽管Flt 3-ITD和Dnmt 3a的诱导性缺失都不能诱导 当我们将Flt 3-ITD突变等位基因与Dnmt 3a的可诱导缺失相结合时， 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 Flt 3-ITD小鼠中Dnmt 3a的可诱导缺失产生了人CN-AML的可靠模型，其可用于 推断构成治疗反应基本生物和分子因素。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CN-AML相比）， 使肿瘤结构和潜在的细胞状态都去卷积。我们希望拟议的研究 以提供具有确定的翻译效用的经验证的FLT 3-ITD/DNMT 3a突变CN-AML鼠模型。

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.