Targeting histone methylation in PTCL

PTCL 中的靶向组蛋白甲基化

• 批准号: 10249204
• 负责人: Sandeep Dave
• 金额: $ 29.81万
• 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/10249204
• 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).

项目摘要 虽然大多数周围T细胞淋巴瘤（PTCL）具有严重的预后，但有几种罕见的亚型 特别致命，预期寿命中位数仅几个月。我们最近研究了三个这样 T细胞淋巴瘤：肝脾淋巴瘤（HSTL），肠病毒相关的T细胞淋巴瘤（EATL）2 和单态上皮型肠道T细胞淋巴瘤（MEITL）。尽管这三种疾病非常 它们的临床表现，病理特征和风险因素不同，它们的特征是高度 重叠的遗传改变。具体而言，这三个肿瘤的沉默频率很高 setD2中的突变和STAT5B中的激活突变。这些常见的机制 突变导致非常不同的表型是该提案的中心主题。我们假设HSTL， EATL和MEITL来自不同的（尽管目前未知）的Origin细胞。这些的共同特征 疾病是它们主要源自γ-戴尔塔T细胞。 T细胞受体信号的作用 在这些肿瘤中，知识很少，将由项目1中的工作告知。此外，SetD2中的突变 可以揭示将在项目3中进一步探索的其他漏洞。定义正常对应物 HSTL，EATL和MEITL可能会更好地了解疾病生物学和机制 这些致命的淋巴瘤的转化。单细胞测序的出现提供了新的 定义产生组织的单个细胞分子谱的方法，并属于 不同的器官。在此提案中，我们试图阐明肝脏，脾脏，佩耶的居民T细胞种群 小鼠和人类中的斑块和肠子，以识别组织中存在的不同T细胞种群 这三个肿瘤从中出现。在AIM 1中，我们将定义三个致命T细胞淋巴瘤的原始细胞： Hstl，Eatl和Meitl。这些研究将定义HSTL，EATL和MEITL的非恶性细胞。 通过单细胞测序方法，并确定setD2和stat5b在T细胞谱系中的影响 发展。在AIM 2中，我们将表征SetD2和STAT5B的个体和组合效应 PTCL中的突变。 SETD2是负责三甲基化组蛋白在组蛋白H3上的三甲基化的主要酶 （H3K36me3）。在同一肿瘤中，我们发现了STAT5B，这是JAK-STAT途径的关键组成部分 T细胞谱系是所有3个亚型中最常激活的癌基因。我们正在体内发展 使我们能够研究这些基因在T细胞谱系中的破坏的小鼠模型。我们建议 研究淋巴瘤启动和谱系承诺的机制。这项工作将利用我们的广泛 使用谱系特异性小鼠模型工作的经验，并表征正常和 恶性细胞。最后，我们将定义所有T细胞的STAT5B和SETD2变化的频谱 淋巴瘤（核B和C）。