Role of novel onco-histone mutations in B-cell malignancies

新型癌组蛋白突变在 B 细胞恶性肿瘤中的作用

基本信息

批准号：
10226944
负责人：
CHARLES DAVID ALLIS
金额：
$ 66.49万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226944
关键词：
Affinity B lymphoid malignancy B-Cell Development B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes BCL2 gene Binding Biochemical Biological Biology Cell Differentiation process Cells Chromatin Complex DNA Data Dependence Development Disease Embryo Epigenetic Process Eukaryotic Cell Follicular Lymphoma Functional disorder Gene Expression Gene Expression Profile Genes Genome Goals Histone H1 Histones Hodgkin Disease Human Immune Immune system Immunoglobulin Somatic Hypermutation Immunoglobulins Investigation Knock-out Linker DNA Lymphoid Lymphoma Lymphomagenesis Maintenance Malignant - descriptor Mature B-Lymphocyte Mediating Memory Methylation Molecular Mus Mutagenesis Mutation Nucleic Acids Nucleosome Core Particle Nucleosomes Oncogenes Pathogenesis Patients Phenotype Plasma Cells Proliferating Property Protein Family Protein Isoforms Proteins Reaction Recurrence Reporting Research Role Sclerosis Signal Transduction Somatic Mutation Structure of germinal center of lymph node T-Lymphocyte Transcriptional Regulation Tumor Suppressor Proteins Up-Regulation Work base blastomere structure carcinogenesis chromatin modification epigenetic regulation epigenome gene repression genetic information genetic signature large cell Diffuse non-Hodgkin&apos s lymphoma loss of function mutant neoplastic novel oncohistone particle recruit response self-renewal stem stem cells tumor virtual

项目摘要

The genetic information encoded in DNA is packaged and interpreted by the cellular machinery within the context of chromatin. As the genome sequence remains largely unchanged throughout development, chromatin modifications represent a critical interface between the genome and regulatory inputs. Histone proteins are major constituents of chromatin; four core histone types make up the nucleosome particle, the basic unit of chromatin. The fifth type, linker histone H1, binds the nucleosome and the linker DNA between. Whereas the progress in understanding the function of core histones is significant in recent years, much of the linker histone H1 biology remains unknown. Mutations in linker histone H1 have been recently reported in approximately 30% of follicular lymphomas and diffuse large B cell lymphomas, and we have identified H1 mutations in 85% of Hodgkin's lymphomas of the nodular sclerosis subtype. Based on preliminary data, we hypothesize that H1 stem restricted dependency clones. B occurring causing cooperates overarching immune this control to tumor isoform loss of function induces lymphomagenesis by ectopically inducing an embryonic cell (ESC) gene expression signature that imparts unlimited self-renewal in GC B-cells that are otherwise in their ability to proliferate. We propose that ESC gene expression frees B-cells from their on T-cell help to survive and divide, resulting in expansion of aberrant pre-neoplastic B-cells Mechanistically, we propose that H1 is involved in PRC2 recruitment and chromatin compaction during cell differentiation, thereby repressing ESC genes. Thus, loss of function of H1 through somatic mutations in germinal center B cells results in reduction and redistribution PRC2 and H3K27 methylation chromatin decompaction and expression of ESC genes. Finally, we predict that H1 loss of function with lymphoma oncogenes such as BCL2 to induce malignant transformation. The goa of the proposed research is to reveal the contributions of linker histones to the humoral response and lymphomagenesis from both biochemical and biological perspectives. We will achieve through the following specific aims: 1) Determine the role and mechanism through which H1 is required to the GC reaction; 2) Determine the mechanism through which H1 mutations reprogram the epigenome drive lymphomagenesis; and 3) Determine whether and how H1 soforms function as bona fide lymphoma suppressors. The study of H1 is quite challenging, but we are uniquely poised to unravel GC canonical l i the molecular details and functional consequences of H1mutations in lymphoid carcinogenesis by bringing together leaders in the field of transcriptional regulation, chromatin, epigenetic regulation and lymphomagenesis.

DNA 中编码的遗传信息由细胞内的细胞机器包装和解释。染色质的上下文。由于基因组序列在整个发育过程中基本保持不变，染色质修饰代表了基因组和调控输入之间的关键界面。组蛋白蛋白质是染色质的主要成分；四种核心组蛋白类型组成核小体颗粒，染色质的基本单位。第五种类型，接头组蛋白 H1，结合核小体和接头 DNA 之间。尽管近年来在理解核心组蛋白功能方面取得了显着进展，但许多接头组蛋白 H1 的生物学特性仍然未知。最近报道了接头组蛋白 H1 的突变大约 30% 的滤泡性淋巴瘤和弥漫性大 B 细胞淋巴瘤，我们已经鉴定出 H1 85% 的结节性硬化症亚型霍奇金淋巴瘤存在突变。根据初步数据，我们假设H1 干受限制的依赖性克隆。乙发生导致合作总体的免疫这控制到瘤同种型功能丧失通过异位诱导胚胎来诱导淋巴瘤发生细胞 (ESC) 基因表达特征，赋予 GC B 细胞无限的自我更新能力，而其他细胞则不然在于它们的增殖能力。我们认为 ESC 基因表达将 B 细胞从其 T 细胞有助于生存和分裂，导致异常肿瘤前期 B 细胞的扩增从机制上讲，我们认为 H1 参与 PRC2 招募和染色质压缩细胞分化，从而抑制 ESC 基因。因此，体细胞突变导致 H1 功能丧失生发中心 B 细胞中的 PRC2 和 H3K27 甲基化减少并重新分布染色质解压缩和 ESC 基因的表达。最后，我们预测H1功能丧失与BCL2等淋巴瘤癌基因结合诱导恶性转化。这拟议研究的目标是揭示连接组蛋白对体液的贡献从生化和生物学的角度来看反应和淋巴瘤发生。我们将实现通过以下具体目标： 1) 确定 H1 需要通过的角色和机制气相色谱反应； 2) 确定H1突变重新编程表观基因组的机制驱动淋巴瘤发生； 3) 确定 H1 soforms 是否以及如何发挥真正的淋巴瘤的作用抑制器。 H1 的研究相当具有挑战性，但我们有独特的能力来解开谜团气相色谱典范我我分子通过汇集领导者来了解淋巴癌发生中 H1 突变的细节和功能后果在转录调控、染色质、表观遗传调控和淋巴瘤发生领域。