A Mouse Model of DNMT3A-Associated Hematologic Malignancy

DNMT3A 相关血液恶性肿瘤的小鼠模型

• 批准号: 9318474
• 负责人: MARGARET A. GOODELL
• 金额: $ 53.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318474
• 关键词: Aberrant DNA Methylation; Affect; Age; Aging; Cells; Collaborations; DNA Methylation; DNA Modification Methylases; DNMT3a; Data; Development; Disease; Disease Outcome; FLT3 gene; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Goals; Hematologic Neoplasms; Hematopoietic stem cells; Human; Lead; Lymphoblastic Leukemia; Malignant Neoplasms; Malignant lymphoid neoplasm; Methylation; Missense Mutation; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Leukemia; Oncogenic; Outcome; Patients; Population; Recording of previous events; Repression; Role; Secondary to; Speed; Stem cells; Suggestion; Transgenes; Transplantation; cell type; insight; leukemia; loss of function mutation; mouse model; mutant; mutant mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; prevent; progenitor; public health relevance; retroviral transduction; self-renewal; stem; whole genome

DESCRIPTION (provided by applicant): Mutations of the de novo DNA methyltransferase 3A (DNMT3A) are associated with multiple hematologic malignancies, including both myeloid and lymphoid leukemias; however, the mechanisms through which such mutations contribute to their development is obscure. Loss of Dnmt3a function in murine hematopoietic stem cells (HSCs) led to dramatic HSC expansion and inhibited differentiation without frank leukemia suggesting the importance of co-occurring mutations in other genes for leukemia development. Here, our overarching goal is to gain insight into the underlying pathophysiologic mechanisms through which DNMT3A mutations alter the course of disease given an otherwise similar mutational profile. We hypothesize that Dnmt3a loss primes stem cells and/or early progenitors for transformation by preventing the repression of stem cell self-renewal genes, inhibiting differentiation, and expanding a target cell population that is then sensitized to the impact of secondary oncogenic hits. We expect that the cellular milieu, in terms of cell type, age, and degree of methylation loss influences the type of leukemia that develops. By investigating the role of Dnmt3a mutations using our mouse model, we hope to elucidate how DNMT3A mutations contribute to an array of malignancies. Toward this goal, we will examine the influence of the mutation type on the generation of myeloid versus lymphoid malignancies using a Dnmt3a-FLT3-ITD model. FLT3-ITD will be introduced into Dnmt3a-mutant HSCs and progenitors and the type and latency of disease generated will be examined. We will also examine the role of the organismal milieu in terms of aging. In addition, we will examine the influence of the target cell type of cooperating FLT3 mutations on the disease outcome. Finally, the mechanism through which Dnmt3a mutation accelerates and alters the impact of FLT3-ITD expression will be examined. Specifically, the whole genome methylation profile and gene expression patterns of similar malignancies with and without Dnmt3a mutations will be compared. Methylation alterations will also be compared with those found in similar human leukemias harboring DNMT3A mutations. Ultimately, these data will allow us to identify the role of DNA methylation broadly, and at specific loci in human leukemia development. Together, these approaches will lend insight into the manner in which DNMT3A mutations promote a variety of human hematologic malignancies and lead to development of new therapeutic approaches for DNMT3A-associated malignancies.

描述（由申请人提供）：从头DNA甲基转移酶3A（DNMT3A）的突变与多种血液学恶性肿瘤有关，包括髓样和淋巴样白血病；但是，这种突变导致其发展的机制晦涩难懂。鼠造血干细胞（HSC）中DNMT3A功能的丧失导致HSC的急剧扩张并抑制分化而没有弗兰克白血病，这表明在其他基因中共生突变在白血病发育中的重要性。在这里，我们的总体目标是深入了解DNMT3A突变的潜在病理生理机制，而D​​NMT3A突变会改变疾病的过程，从而鉴于相似的突变特征。我们假设DNMT3A损失素干细胞和/或早期祖细胞通过防止干细胞自我更新基因的抑制，抑制分化并扩大目标细胞群体，从而对继发性致癌性命中的影响进行敏感。我们预计，就细胞类型，年龄和甲基化损失程度而言，细胞环境会影响发展的白血病类型。通过使用我们的小鼠模型研究DNMT3A突变的作用，我们希望阐明DNMT3A突变如何促进一系列恶性肿瘤。为了实现这一目标，我们将使用DNMT3A-FLT3-ITD模型研究突变类型对髓样生成与淋巴恶性肿瘤的影响。 FLT3-ITD将被引入DNMT3A突变的HSC和祖细胞中，并将检查产生的疾病的类型和潜伏期。我们还将在衰老方面研究生物环境的作用。此外，我们将研究合作FLT3突变的靶细胞类型对疾病结果的影响。最后，将研究DNMT3A突变加速并改变FLT3-ITD表达的影响的机制。具体而言，将比较有或没有DNMT3A突变的类似恶性肿瘤的整个基因组甲基化谱和基因表达模式。还将将甲基化改变与具有DNMT3A突变的类似人类白血病中的甲基化改变。最终，这些数据将使我们能够广泛地鉴定DNA甲基化的作用，以及在人类白血病发育中的特定基因座。这些方法一起，将深入了解DNMT3A突变促进各种人类血液学恶性肿瘤的方式，并导致开发与DNMT3A相关的恶性肿瘤的新治疗方法。