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 弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）起源于生发中心（GC）B细胞; 前体B细胞经历多轮增殖阶段，通过体细胞免疫编辑它们的免疫球蛋白 超突变和类别转换重组，然后通过与T滤泡相互作用进行亲和选择 辅助（Tfh）细胞和滤泡树突细胞（FDC）。进入和退出GC反应需要 由转录因子控制的基因表达的广泛变化，这些转录因子招募共激活因子或共激活因子， 阻遏物驱动表观遗传和转录变化。这些分子程序的失调 干扰正常的B细胞分化并促成FL/DLBCL。先前的研究表明（a）EZH 2 调节GC B细胞的过度增殖性质和（B）EZH 2 Y 641残基的功能获得性突变 通过减弱GC B细胞对Tfh细胞帮助的需求并改变依赖性来“启动”淋巴瘤发生 通过增加B细胞与这些基质细胞界面的受体表达而转化为FDC。 Ezh 2 Y 641 F GC B细胞逃避Tfh导向的克隆选择和亲和力成熟以逃避Tfh介导的 消除，导致淋巴瘤形成。值得注意的是，与EZH 2 WT相比，携带EZH 2 Y 641 F的GC B细胞显示出 分别增加和减少BAFFR和CD 40表达，并逃避CD 40 L介导的阻断。 GC反应受损。目前尚不清楚Tfh的损伤是否表现为Tfh的调节障碍。 Tfh-B免疫突触（IS）的机械控制及其细胞间受体-配体的改变 FL/DLBCL中的相互作用和信号传导。最重要的假设是，与GC B细胞相比， EZH 2 WT，GCB DLBCL/FL中的EZH 2 Y 641突变导致介导免疫调节的关键免疫受体失调 GC B细胞与Tfh细胞和FDC的相互作用表现为受体力、配体结合和 机械传导失调的受体机械生物学影响下游B细胞信号传导， 表观遗传学和淋巴微环境线索的传感负责熄灭“假- GC B细胞的“恶性”表型，从而驱动B细胞的癌性转化。我们的转录组 分析表明，参与B-FDC和B-Tfh相互作用的蛋白质水平发生了变化， 影响细胞功能。我们的目标是了解DLBCL/FL驱动的动态表观遗传状态是如何改变的。 EZH 2 Y 641突变使B细胞机械生物学失调，导致恶性肿瘤。