Targeting histone methylation in PTCL

项目总结 虽然大多数外周T细胞淋巴瘤(PTCL)预后不佳，但也有几种罕见的亚型 尤其致命，平均预期寿命只有几个月。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 和单形性上皮嗜性T细胞淋巴瘤(MEITL)。虽然这三种疾病都很严重 不同的临床表现、病理特征和危险因素，具有高度的特点 重叠的基因改变。具体地说，这三种肿瘤都有很高的沉默频率 SETD2的突变和STAT5B的激活突变。通过这些共同的机制 突变导致非常不同的表型是这一提议的中心主题。我们假设HSTL， EATL和MEITL起源于不同的、但目前尚不清楚的起源细胞。这些产品的一个共同特点是 疾病的主要原因是它们主要来源于伽马-德尔塔T细胞。T细胞受体信号转导的作用 在这些肿瘤中的作用知之甚少，并将通过项目1的工作得到信息。此外，SETD2的突变 可能揭示其他漏洞，这些漏洞将在项目3中进一步探讨。定义正常的对应项 对HSTL、EATL和MEITL的研究可能有助于更好地了解疾病生物学和发病机制。 这些致命性淋巴瘤背后的转化。单细胞测序的出现提供了新的 确定单个细胞的分子轮廓的方法，这些细胞产生组织并驻留在 不同的器官。在这个方案中，我们试图阐明肝、脾、Peyer‘s的常驻T细胞群 在小鼠和人的肠道和补丁中识别组织中存在的不同T细胞群 这三种肿瘤就是由此产生的。在目标1中，我们将定义三种致命性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的非恶性起源细胞 通过单细胞测序方法确定SETD2和STAT5B在T细胞谱系中的作用 发展。在目标2中，我们将描述SETD2和STAT5B的单独和联合作用 PTCL基因突变。SETD2是组蛋白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，是所有三种亚型中最常被激活的癌基因。我们在活体内发育 小鼠模型，使我们能够研究这些基因在T细胞谱系中的错位。我们建议 研究淋巴瘤的发病机制和谱系承诺。这项工作将利用我们广泛的 使用谱系特定的小鼠模型并表征正常和 恶性细胞。最后，我们将定义所有T细胞中STAT5B和SETD2改变的谱 淋巴瘤(核心为B和C)。

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).