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.

编码在DNA中的遗传信息被包装并由细胞内的细胞机制解释