A Mouse Model of DNMT3A-Associated Hematologic Malignancy

DNMT3A 相关血液恶性肿瘤的小鼠模型

基本信息

批准号：
8761773
负责人：
MARGARET A. GOODELL
金额：
$ 53.48万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/8761773
关键词：
A Mouse Aberrant DNA Methylation Affect Age Aging Cells Collaborations DNA Methylation DNA Methyltransferase DNA Modification Methylases Data Development Disease Disease Outcome FLT3 gene Gene Expression Gene Expression Profile Generations Genes Genome Goals Hematologic Neoplasms Hematopoietic stem cells Human Human Development 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 Transgenes Transplantation cell type human DNA 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

项目摘要

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) 的突变与多种血液恶性肿瘤相关，包括骨髓性和淋巴性白血病；然而，此类突变促进其发育的机制尚不清楚。小鼠造血干细胞 (HSC) 中 Dnmt3a 功能的丧失导致 HSC 急剧扩增并抑制分化，但没有明显的白血病，这表明其他基因中同时发生的突变对于白血病发展的重要性。在这里，我们的首要目标是深入了解 DNMT3A 突变在其他相似突变谱的情况下改变病程的潜在病理生理机制。我们假设 Dnmt3a 缺失通过防止干细胞自我更新基因的抑制、抑制分化和扩大靶细胞群来启动干细胞和/或早期祖细胞的转化，从而使靶细胞群对继发性致癌打击的影响敏感。我们预计，细胞环境（细胞类型、年龄和甲基化缺失程度）会影响白血病的类型。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 突变如何导致一系列恶性肿瘤。为了实现这一目标，我们将使用 Dnmt3a-FLT3-ITD 模型检查突变类型对髓系恶性肿瘤与淋巴系恶性肿瘤生成的影响。 FLT3-ITD 将被引入 Dnmt3a 突变型 HSC 和祖细胞中，并检查产生的疾病的类型和潜伏期。我们还将研究有机环境在衰老方面的作用。此外，我们将研究FLT3协同突变的靶细胞类型对疾病结果的影响。最后，将检查 Dnmt3a 突变加速和改变 FLT3-ITD 表达影响的机制。具体来说，将比较具有和不具有 Dnmt3a 突变的类似恶性肿瘤的全基因组甲基化谱和基因表达模式。甲基化改变也将与具有 DNMT3A 突变的类似人类白血病中发现的甲基化改变进行比较。最终，这些数据将使我们能够广泛确定 DNA 甲基化在人类白血病发展中特定位点的作用。总之，这些方法将有助于深入了解 DNMT3A 突变促进多种人类血液恶性肿瘤的方式，并导致开发 DNMT3A 相关恶性肿瘤的新治疗方法。