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: 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
• 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' s lymphoma; loss of function; mutant; neoplastic; novel; oncohistone; 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.

DNA中编码的遗传信息是由细胞机制包装和解释的 染色质的上下文。由于基因组序列在整个发育过程中都保持不变，因此 染色质修饰代表基因组和调节输入之间的关键接口。组蛋白 蛋白质是染色质的主要成分。四种核心组蛋白类型构成核小体粒子， 染色质的基本单位。第五类的接头组蛋白H1结合核小体和接头DNA之间。 近年来，理解核心组蛋白功能的功能的进展是显着的，但大部分 接头组蛋白H1生物学仍然未知。最近已经报道了接头组蛋白H1中的突变 大约30％的卵泡淋巴瘤和扩散的大B细胞淋巴瘤，我们已经鉴定出H1 霍奇金的霍奇金淋巴结杆菌的85％的突变。根据初步数据，我们 假设该H1 干 受限制的 依赖性 克隆。 b 发生 引起 合作 总体 免疫 这 控制 到 瘤 同工型的功能损失通过异位诱导胚胎诱导淋巴作用 细胞（ESC）基因表达签名，在GC B细胞中赋予无限自我更新 他们的扩散能力。我们建议ESC基因表达使B细胞从其 在T细胞帮助生存和分裂的情况下，导致异常肿瘤前B细胞的扩大 从机械上讲，我们建议H1参与PRC2募集和染色质压实 细胞分化，从而抑制ESC基因。因此，通过体细胞突变的H1功能丧失 在生发中心中心的B细胞导致减少和重新分布PRC2和H3K27甲基化 ESC基因的染色质分解和表达。最后，我们预测H1功能丧失 淋巴瘤癌基因（例如BCL2）诱导恶性转化。这 拟议研究的果阿是揭示连接器组蛋白对体液的贡献 从生化和生物学角度的反应和淋巴作用。我们将实现 通过以下特定目的：1）确定需要H1的作用和机制 GC反应； 2）确定H1突变重新编程表观基因组的机制 驱动淋巴作用； 3）确定H1 Soforms是否以及如何充当真正的淋巴瘤 抑制器。对H1的研究非常具有挑战性，但我们完全准备拆卸 GC 典范 l 我 分子 H1Mutation在淋巴癌变中的细节和功能后果，通过将领导者汇总在一起 在转录调节，染色质，表观遗传调节和淋巴作用的领域。