Dysregulated mechanoimmunology of epigenetics-driven lymphomas

表观遗传学驱动的淋巴瘤的机械免疫学失调

• 批准号: 10669928
• 负责人: Ankur Singh
• 金额: $ 53.26万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669928
• 关键词: Actomyosin; Affect; Affinity; Antigens; Automobile Driving; B cell differentiation; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological; Biological Assay; Biomechanics; Biophysics; Cancerous; Cell Communication; Cell physiology; Cell surface; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cues; Defect; Dependence; Drug Targeting; EZH2 gene; Engineering; Enzymes; Epigenetic Process; Event; Exhibits; Extracellular Matrix; Follicular Dendritic Cells; Follicular Lymphoma; Gene Expression; Generations; Genetic Transcription; Genetically Engineered Mouse; Goals; Helper-Inducer T-Lymphocyte; Histones; Immune; Immune response; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunotherapy; Impairment; Ligand Binding; Ligands; Lymphoid; Lymphoma; Lymphoma cell; Lymphomagenesis; Magnetism; Malignant - descriptor; Malignant Neoplasms; Mechanics; Mediating; Molecular; Mutation; Nature; Pathogenesis; Patients; Phenotype; Process; Proliferating; Proteins; Reaction; Regulation; Role; Signal Induction; Signal Transduction; Somatic Mutation; Stromal Cells; Structure of germinal center of lymph node; Surface; TNFRSF5 gene; TNFSF5 gene; Time; cancer cell; efficacy testing; epigenetic therapy; epigenome; gain of function mutation; genetic corepressor; histone methyltransferase; immunoengineering; immunological synapse; immunological synapse formation; large cell Diffuse non-Hodgkin' s lymphoma; lymph nodes; mechanotransduction; novel; physical science; premalignant; programs; receptor; receptor expression; recruit; response; single molecule; synergism; targeted agent; transcription factor; transcriptomics; tumor xenograft

PROJECT SUMMARY Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) arise from germinal center (GC) B cells; a stage at which precursor B cells undergo rounds of proliferation, edit their immunoglobulins by somatic hypermutation and class-switch recombination, followed by affinity selection via interactions with T follicular helper (Tfh) cells and follicular dendritic cells (FDCs). The entry to, and exit from, the GC reaction requires extensive changes in gene expression that are controlled by transcription factors that recruit co-activators or co- repressors that drive epigenetic and transcriptional changes. The dysregulation of these molecular programs perturbs the normal B cell differentiation and contributes to FL/DLBCLs. Prior studies indicate that (a) EZH2 regulates the hyperproliferative nature of GC B cells and (b) gain-of-function mutations of the EZH2 Y641 residue “initiate” lymphomagenesis by attenuating GC B cell requirement for Tfh cell help and shifting the dependency to FDCs through increased expression of receptors through which B-cells interface with these stromal cells. Ezh2Y641F GC B cells evade Tfh-directed clonal selection and affinity maturation to escape Tfh-mediated elimination, leading to lymphomagenesis. Notably, compared to EZH2WT, GC B cells carrying Ezh2Y641F show increased and decreased BAFFR and CD40 expressions, respectively, and escape CD40L blockade-mediated impairment of GC reaction. It is unclear whether the impairment of Tfh help manifests as dysregulation of the mechanical control of Tfh–B immunological synapse (IS) and alteration of their intercellular receptor-ligand interactions and signaling in FL/DLBCLs. The overarching hypothesis is that in contrast to GC B cells with EZH2WT, the EZH2Y641 mutation in GCB DLBCL/FL results in dysregulation of key immunoreceptors mediating the interactions of GC B cells with Tfh cells and FDCs manifesting as altered receptor forces, ligand binding, and mechanotransduction. The dysregulated receptor mechanobiology impacts downstream B cell signaling, epigenetics, and sensing of lymphoid microenvironmental cues responsible for extinguishing the “pseudo- malignant” phenotype of GC B cells, thereby driving the cancerous transformation of B cells. Our transcriptomic analysis suggests changes in the levels of proteins involved in B–FDC and B–Tfh interactions, which should affect cellular function. The goal is to understand how the dynamic epigenetic states of DLBCL/FL-driving EZH2Y641 mutations dysregulate B cell mechanobiology, leading to malignancy.

项目摘要 扩散的大B细胞淋巴瘤（DLBCL）和Follic淋巴瘤（FL）来自生发中心（GC）B细胞； 阶段的阶段，在增殖圆下，前体B细胞，通过躯体编辑其免疫球蛋白 超名和类切换重组，然后通过与T卵泡相互作用进行亲和力选择 助手（TFH）细胞和卵泡树突状细胞（FDC）。进入并退出GC反应需要 受转录因子控制的基因表达的广泛变化，这些因子募集了共激活因子或共同激活因子 驱动表观遗传和转录变化的阻遏物。这些分子程序的失调 正常B细胞​​分化，并导致FL/DLBCL。先前的研究表明（a）ezh2 调节GC B细胞的过度增殖性质和（b）EZH2 Y641住所的功能增益突变 通过减轻GC B细胞的TFH细胞帮助并转移依赖性，“启动”淋巴作用 通过增加接收器的表达来通过B细胞与这些基质细胞的接口通过增加的表达。 EZH2Y641F GC B细胞逃避TFH指导的克隆选择和亲和力成熟以逃脱TFH介导的 消除，导致淋巴作用。值得注意的是，与携带EZH2Y641F的EZH2WT相比 分别增加和增加了BAFFR和CD40表达式，并逃脱CD40L封锁介导的 GC反应受损。目前尚不清楚TFH的损害是否有助于表现为失调 TFH – B免疫突触（IS）的机械控制及其细胞间接收器配体的改变 FL/DLBCL中的相互作用和信号传导。总体假设是，与GC B细胞相比 EZH2WT，GCB DLBCL/FL中的EZH2Y641突变导致关键免疫受体的失调 GC B细胞与TFH细胞和FDC的相互作用表现为受体作用改变，配体结合和 机械转导。失调的受体机制影响下游B细胞信号传导， 表观遗传学和淋巴微环境提示的敏感性，负责熄灭“伪 GC B细胞的恶性”表型，从而驱动B细胞的取消转化。我们的转录组学 分析表明，B – FDC和B – TFH相互作用中涉及的蛋白质水平的变化，应 影响细胞功能。目的是了解DLBCL/FL驾驶的动态表观遗传状态 EZH2Y641突变失调B细胞机制，导致恶性肿瘤。