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

• 批准号: 9981709
• 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
• 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/9981709
• 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' s lymphoma; loss of function; mutant; neoplastic; novel; particle; recruit; response; self-renewal; stem; stem cells; tumor; virtual

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.

编码在DNA中的遗传信息由细胞内的细胞机制包装和解释。 染色质的背景。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节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，连接组蛋白H1，结合核小体和之间的连接DNA。 尽管近年来对核心组蛋白功能的理解取得了重大进展，但许多研究都表明， 接头组蛋白H1生物学仍然未知。最近有报道称，连接体组蛋白H1的突变发生在 大约30%的滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤，我们已经确定了H1 在85%的结节硬化型霍奇金淋巴瘤中存在突变。根据初步数据，我们 假设H1 干 限制 依赖 克隆 B 发生 造成 合作 总体 免疫 这 控制 到 肿瘤 同种型功能丧失通过异位诱导胚胎淋巴瘤形成而诱导淋巴瘤发生 细胞（ESC）基因表达特征，赋予GC B细胞无限的自我更新，否则 它们的增殖能力。我们认为ESC基因的表达使B细胞从它们的 帮助T细胞存活和分裂，导致异常的癌前B细胞扩增 从机制上讲，我们认为H1参与了PRC 2的募集和染色质的致密化， 细胞分化，从而抑制ESC基因。因此，通过体细胞突变导致的H1功能丧失 在生殖中心B细胞中，PRC 2和H3 K27甲基化减少并重新分布 染色质解聚和ESC基因的表达。最后，我们预测H1功能丧失 与淋巴瘤癌基因如BCL 2一起诱导恶性转化。的 这项研究的果阿是揭示连接组蛋白对体液免疫应答的贡献。 从生物化学和生物学的角度来看，反应和淋巴瘤的发生。我们将实现 通过以下具体目标：1）确定H1的角色和机制， GC反应; 2）确定H1突变重编程表观基因组的机制 驱动淋巴瘤发生; 3）确定H1亚型是否以及如何作为真正的淋巴瘤发挥作用 抑制剂H1的研究是相当具有挑战性的，但我们是独一无二的准备解开 GC canonical L 我 分子 通过将领导者聚集在一起，研究淋巴癌发生中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。