Role of Siglec-10/G as a tumor suppressor in B-cells

Siglec-10/G 作为 B 细胞肿瘤抑制剂的作用

• 批准号: 9224943
• 负责人: Matthew Scott Macauley
• 金额: $ 13.18万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224943
• 关键词: Affect; Age; Antibodies; Antibody Affinity; Autoimmunity; B-Cell Activation; B-Cell Development; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding; Blocking Antibodies; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cells; Characteristics; Chimera organism; Coculture Techniques; Development; Enhancing Lesion; Epigenetic Process; Etiology; Event; Family; GTP-Binding Protein alpha Subunits, Gs; Glycolipids; Glycoproteins; Goals; Helper-Inducer T-Lymphocyte; Human; Hyperplasia; Immune; Immunity; Immunoglobulin Somatic Hypermutation; Immunoglobulins; In Vitro; Kinetics; Knowledge; Lectin; Ligands; Link; Lymphoma; Lymphomagenesis; Malignant - descriptor; Modeling; Mus; Orthologous Gene; Pattern; Phenotype; Play; Polysaccharides; Predisposition; Process; Reaction; Receptor Cell; Receptors, Antigen, B-Cell; Role; Sialic Acids; Somatic Mutation; Specificity; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; cytokine; experimental study; glycosylation; insight; member; mouse model; overexpression; pathogen; prevent; receptor; response; sialic acid binding Ig-like lectin; stem; treatment strategy

PROJECT SUMMARY/ABSTRACT Approximately 80% of B-cell non-Hodgkin's lymphomas are derived from germinal center (GC) B-cells. Somatic hypermutation within GC B-cells is necessary for antibody affinity maturation, but somatic mutations can also drive epigenetic lesions that enhance survival, maintain the hyperproliferative state of GC B-cells, and promote lymphomagenesis. Given the susceptibility of GC B-cells to malignant transformation, it is not surprising that the natural process of selection within the GC is thought to help protect against the selection of malignant clones. Accordingly, a deeper understanding of factors that restrain the GC are needed. Siglec- 10/G (human/mouse ortholog) are members of the Siglec family of inhibitory receptors that recognize sialic acid-containing glycan ligands. Siglec-10/G dampen B-cell activation through the B-cell receptor. In mice, the role of Siglec-G in inhibiting the initial events of B-cell activation have been described, but it is unknown if Siglec-G plays a role at later stages, such as in the GC. Interestingly, an expanded GC compartment is observed in Siglec-G-/- mice, Siglec-G-/- mice develop B-cell lymphomas, and Siglec-10 expression is lost on GC-derived B-cell lymphomas. Taken together, we hypothesize that Siglec-G restrains the GC reaction under healthy conditions and that loss of Sigelc-10/G expression promotes the development of GC-derived B-cell lymphomas due to a poorly controlled GC reaction. Preliminary results support a role for Siglec-G in restraining GC B-cells, as B-cell responses in mixed bone marrow chimeras reveal that Siglec-G-/- GC B-cells gradually outcompete WT GC B-cells. Additional preliminary evidence demonstrates a unique phenotype (increased ICOS expression) in GC T-follicular helper (GC-Tfh) cells within Siglec-G-/- mice, supporting other lines of evidence for a role for Siglec-G in modulating B-T cell interactions. This project aims to investigate a causal relationship between loss of Siglec-G and the development of GC-derived B-cell lymphomas and assess a potential role for Siglec-G in regulating B-T cell interactions. Two independent approaches will be used to test causality between loss of Siglec-G-/-, a dysregulated GC, and the development of GC-derived B- cell lymphomas. In the first approach, Tfh cells will be ablated in Siglec-G-/- mice. In the second approach, Siglec-G expression will be maintained transgenically in an independent mouse model that develops GC- derived B-cell lymphomas and loose Siglec-G expression. To examine a role for Siglec-G as a negative regulator of B-T cell interactions, the ligand specificity of Siglec-G will be dissected in reference to glycans on naïve GC-Tfh CD4+ cells, and glycan ligands on CD4+ T-cells will be manipulated to examine what impact this has on B-T cell interactions. The overall objective of this project is to test the role of Siglec-G as a tumor suppressor in GC B-cells and examine one potential mechanism by which Siglec-G restrains the GC. This knowledge will lead to new insights into the etiology of GC-derived B-cell lymphomas, and potentially offer clues for new treatment strategies, which are especially needed for the incurable FL.

项目总结/摘要 大约80%的B细胞非霍奇金淋巴瘤源自生发中心（GC）B细胞。 GC B细胞内的体细胞超突变是抗体亲和力成熟所必需的，但体细胞突变 也可以驱动表观遗传损伤，提高生存率，维持GC B细胞的过度增殖状态， 促进淋巴瘤的发生。鉴于GC B细胞对恶性转化的易感性， 令人惊讶的是，GC内的自然选择过程被认为有助于防止选择， 恶性克隆因此，需要更深入地了解制约GC的因素。Siglec- 10/G（人/小鼠直系同源物）是识别唾液酸的Siglec抑制性受体家族的成员。 含酸聚糖配体。Siglec-10/G通过B细胞受体抑制B细胞活化。在小鼠中， 已经描述了Siglec-G在抑制B细胞活化的初始事件中的作用，但尚不清楚是否 Siglec-G在后期发挥作用，例如在GC中。有趣的是，一个扩大的GC室， 在Siglec-G-/-小鼠中观察到，Siglec-G-/-小鼠发生B细胞淋巴瘤，并且Siglec-10表达在B细胞淋巴瘤中丢失。 GC衍生的B细胞淋巴瘤。综上所述，我们假设Siglec-G抑制了GC反应， 健康条件和Sigelc-10/G表达丧失促进GC衍生的B细胞的发育 淋巴瘤由于控制不良的GC反应。初步结果支持Siglec-G在以下方面的作用： 抑制GC B细胞，因为混合骨髓嵌合体中的B细胞反应表明Siglec-G-/- GC B细胞 逐渐胜过WT GC B细胞。额外的初步证据证明了一种独特的表型 在Siglec-G-/-小鼠内的GC T-滤泡辅助细胞（GC-Tfh）中，ICOS表达增加，支持其他 Siglec-G在调节B-T细胞相互作用中的作用的证据线。该项目旨在调查一个 Siglec-G缺失与GC源性B细胞淋巴瘤发生之间的因果关系， 评估Siglec-G在调节B-T细胞相互作用中的潜在作用。两种独立的方法将 用于检测Siglec-G-/-（一种失调的GC）缺失与GC衍生B-表达之间的因果关系。 细胞淋巴瘤在第一种方法中，将在Siglec-G-/-小鼠中消融Tfh细胞。在第二种方法中， Siglec-G表达将在发展GC-1的独立小鼠模型中转基因维持。 衍生的B细胞淋巴瘤和松散的Siglec-G表达。检查Siglec-G作为阴性的作用 作为B-T细胞相互作用的调节剂，Siglec-G的配体特异性将参照聚糖进行剖析， 将操作幼稚GC-Tfh CD 4+细胞和CD 4 + T细胞上的聚糖配体，以检查这对CD 4 + T细胞的影响。 与B-T细胞的相互作用有关。该项目的总体目标是测试Siglec-G作为肿瘤的作用 在GC B-细胞中的抑制子，并检查Siglec-G抑制GC的一种潜在机制。这 知识将导致对GC衍生的B细胞淋巴瘤的病因学的新见解，并可能提供 新的治疗策略的线索，这是特别需要为无法治愈的FL。