Targeting histone methylation in PTCL

PTCL 中的靶向组蛋白甲基化

• 批准号: 9791868
• 负责人: Sandeep Dave
• 金额: $ 31.76万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791868
• 关键词: Biological; Biology; Cell Lineage; Cells; Clinical; Data; Development; Disease; Enzymes; Frequencies; Genes; Genetic; Histone H3; Human; Immune; Individual; Intestines; Knock-out; Lead; Life Expectancy; Liver; Lymphoma; Lymphomagenesis; Lysine; Malignant - descriptor; Molecular Profiling; Mus; Mutation; Non-Malignant; Normal Cell; Oncogenes; Organ; Pathologic; Pathway interactions; Peripheral; Phenotype; Population; Receptor Signaling; Risk Factors; Role; STAT5B gene; Spleen; Structure of aggregated lymphoid follicle of small intestine; T-Cell Development; T-Cell Lymphoma; T-Cell Receptor; T-Lymphocyte; Tissues; Transgenic Mice; Tumor Suppressor Genes; Work; cancer cell; cell behavior; experience; histone methylation; histone methyltransferase; in vivo; mouse model; novel strategies; novel therapeutic intervention; outcome forecast; overexpression; single cell sequencing; tumor; γδ T cells

PROJECT SUMMARY While most peripheral T-cell lymphomas (PTCLs) carry a grim prognosis, there are several rare subtypes that are particularly lethal, with a median life expectancy of only a few months. We have recently studied three such T-cell lymphomas: hepatosplenic T-cell lymphoma (HSTL), enteropathy-associated T-cell lymphoma (EATL)2 and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Although these three diseases are very different in their clinical presentation, pathologic features and risk factors, they are characterized by highly overlapping genetic alterations. Specifically, all three of these tumors have high frequencies of silencing mutations in SETD2 and activating mutations in STAT5B. The mechanisms through which these common mutations lead to very distinct phenotypes are a central theme in this proposal. We hypothesize that HSTL, EATL and MEITL arise from distinct, though currently unknown, cells-of-origin. A common feature of these diseases is that they are predominantly derived from gamma-delta T cells. The role of T-cell receptor signaling in these tumors is poorly understood and will be informed by the work in Project 1. Further, mutations in SETD2 could reveal additional vulnerabilities that will be explored further in Project 3. Defining the normal counterparts of HSTL, EATL, and MEITL may provide a better understanding of the disease biology and the mechanisms of transformation underlying these lethal lymphomas. The advent of single-cell sequencing provides new approaches for defining the molecular profiles of individual cells that give rise to tissues and are resident in different organs. In this proposal, we seek to elucidate the resident T-cell populations of the liver, spleen, Peyer's patch and intestine in mouse and humans to identify different T-cell populations that are present in the tissues from which these three tumors arise. In Aim 1, we will define the cell-of-origin of three lethal T-cell lymphomas: HSTL, EATL and MEITL. These studies will define the nonmalignant cell-of-origin of HSTL, EATL and MEITL through single-cell sequencing approaches and determine the effects of SETD2 and STAT5B in T-cell lineage development. In Aim 2, we will characterize the individual and combined effects of SETD2 and STAT5B mutations in PTCLs. SETD2 is the primary enzyme responsible for trimethylation of lysine 36 on histone H3 (H3K36me3). In the same tumors, we have found STAT5B, a critical component of the JAK-STAT pathway in the T-cell lineage, to be the most frequently activated oncogene across all 3 subtypes. We are developing in vivo mouse models that enable us to study the derangement of these genes in the T-cell lineage. We propose to study the mechanisms of lymphoma initiation and lineage commitment. This work will utilize our extensive experience working with lineage-specific mouse models and characterizing immune cell behavior in normal and malignant cells. Finally, we will define the spectrum of STAT5B and SETD2 alterations across all T-cell lymphomas (with Cores B and C).

项目摘要 虽然大多数外周T细胞淋巴瘤（PTCL）预后很差，但有几种罕见的亚型， 特别致命，平均寿命只有几个月。我们最近研究了三个这样的 T细胞淋巴瘤：肝脾T细胞淋巴瘤（HSTL）、肠病相关T细胞淋巴瘤（EATL）2 和单形性亲上皮性肠T细胞淋巴瘤（MEITL）。虽然这三种疾病都非常 不同的临床表现，病理特征和危险因素，他们的特点是高度 重叠的遗传变异具体来说，这三种肿瘤都有很高的沉默频率， SETD 2中的突变和STAT 5 B中的激活突变。这些共同的机制 突变导致非常不同的表型是该提议的中心主题。我们假设HSTL， EATL和MEITL产生于不同的，虽然目前未知的，细胞的起源。其中一个共同特点是 疾病的另一个重要原因是它们主要来源于γ-δ T细胞。T细胞受体信号的作用 在这些肿瘤中的作用知之甚少，将通过项目1的工作得到信息。此外，SETD 2中的突变 可能会揭示更多的漏洞，这些漏洞将在项目3中进一步探讨。定义正常对应物 HSTL，EATL和MEITL的研究可能会更好地了解疾病生物学和 这些致命的淋巴瘤背后的转化。单细胞测序的出现提供了新的 用于定义产生组织并驻留在细胞中的单个细胞的分子谱的方法， 不同的器官在这个提议中，我们试图阐明肝、脾、派伊尔氏淋巴结炎和淋巴结炎的常驻T细胞群。 贴片和肠中的小鼠和人类，以确定不同的T细胞群，存在于组织中 这三种肿瘤的起源在目标1中，我们将定义三种致死性T细胞淋巴瘤的起源细胞： HSTL、EATL和MEITL。这些研究将确定HSTL，EATL和MEITL的非恶性细胞来源 通过单细胞测序方法，并确定SETD 2和STAT 5 B在T细胞谱系中的作用 发展在目标2中，我们将表征SETD 2和STAT 5 B的单独和组合效应。 PTCL中的突变。SETD 2是负责组蛋白H3上赖氨酸36三甲基化的主要酶 （H3K36me3）。在相同的肿瘤中，我们发现STAT 5 B，JAK-STAT通路的关键组分， T细胞谱系，是所有3种亚型中最频繁激活的癌基因。我们正在体内开发 小鼠模型使我们能够研究T细胞谱系中这些基因的紊乱。我们建议 研究淋巴瘤发生和谱系定型的机制。这项工作将利用我们广泛的 具有谱系特异性小鼠模型的工作经验，并在正常和 恶性细胞最后，我们将定义所有T细胞中STAT 5 B和SETD 2改变的谱。 淋巴瘤（具有核心B和C）。