Targeting histone methylation in PTCL

PTCL 中的靶向组蛋白甲基化

• 批准号: 10477033
• 负责人: Sandeep Dave
• 金额: $ 29.22万
• 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/10477033
• 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; Peyer' s Patches; Phenotype; Population; Prognosis; Receptor Signaling; Risk Factors; Role; STAT5B gene; Spleen; 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; 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).

项目概要 虽然大多数外周 T 细胞淋巴瘤 (PTCL) 的预后很严峻，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 和单形性上皮性肠 T 细胞淋巴瘤 (MEITL)。虽然这三种疾病非常严重 其临床表现、病理特征和危险因素各不相同，其特点是高度 重叠的基因改变。具体来说，所有这三种肿瘤都具有高频率的沉默 SETD2 突变和 STAT5B 激活突变。这些共同的机制 突变导致非常独特的表型是该提案的中心主题。我们假设 HSTL， EATL 和 MEITL 源自不同的（尽管目前未知）起源细胞。这些的一个共同特点是 疾病的一个特点是它们主要源自 γ-δ T 细胞。 T 细胞受体信号传导的作用 目前对这些肿瘤中的突变知之甚少，项目 1 中的工作将提供相关信息。此外，SETD2 中的突变 可能会揭示其他漏洞，这些漏洞将在项目 3 中进一步探讨。定义正常对应项 HSTL、EATL 和 MEITL 的研究可以帮助我们更好地了解疾病生物学和机制 这些致命淋巴瘤的转化。单细胞测序的出现提供了新的 定义产生组织并驻留在体内的单个细胞的分子谱的方法 不同的器官。在本提案中，我们试图阐明肝脏、脾脏、派尔氏淋巴管的常驻 T 细胞群。 小鼠和人类的斑块和肠道，以识别组织中存在的不同 T 细胞群 这三种肿瘤都是由此产生的。在目标 1 中，我们将定义三种致死性 T 细胞淋巴瘤的细胞起源： HSTL、EATL 和 MEITL。这些研究将定义 HSTL、EATL 和 MEITL 的非恶性细胞起源 通过单细胞测序方法确定 SETD2 和 STAT5B 在 T 细胞谱系中的影响 发展。在目标 2 中，我们将描述 SETD2 和 STAT5B 的单独效应和组合效应 PTCL 突变。 SETD2 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，我们发现了 STAT5B，它是 JAK-STAT 通路的关键组成部分。 T 细胞谱系，是所有 3 种亚型中最常激活的癌基因。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 拥有使用谱系特异性小鼠模型以及表征正常和正常情况下免疫细胞行为的经验 恶性细胞。最后，我们将定义所有 T 细胞中 STAT5B 和 SETD2 改变的范围 淋巴瘤（核心 B 和 C）。