HVEM-BTLA Pathway in Lymphoma

描述(申请人提供)：新出现的证据表明，免疫和炎症细胞因子途径促进淋巴瘤的发展和进展，但分子机制尚不清楚。肿瘤坏死因子受体超家族成员hvem(疱疹病毒进入介体，TNFRSF14)和免疫球蛋白超家族蛋白BTLA(B和T淋巴细胞衰减器)组成了一个新的信号网络，调节淋巴细胞的激活和增殖。重要的是，最近对人类淋巴瘤和相关的血液恶性肿瘤的遗传学分析显示，Hvem和BTLA的频繁体细胞突变与预后不良有关。我们的研究提供了新的证据，表明在人类淋巴瘤中发现的HVEM体细胞点突变特异性地改变了配体的结合，可能影响内在的NFκB生存途径和免疫调节机制。我们发现了一种新的转录调控途径，它下调BTLA，这可能是抑制B和T淋巴瘤细胞BTLA表达的原因。Hvem-BTLA途径虽然在宿主防御中得到了很好的认识，但在癌症的背景下却没有明确的定义。HVEM-BTLA途径的增殖抑制功能和频繁的体细胞突变提示，hVEM-BTLA通路可能是血液病发生发展的一个检验点。在这个项目中，我们将确定人类淋巴瘤细胞系中HVEM和BTLA通路失调的分子机制。在B细胞恶性肿瘤的小鼠模型中检测了hvem-BTLA途径的影响。已经开发了一系列与hvem-BTLA相关的细胞因子的抗体和基于受体的激动剂和拮抗剂，并且hvem和BTLA基因缺失和条件缺失的小鼠可用于补充人类淋巴瘤细胞的结果。总之，这些目的是将人类淋巴瘤中hvem-BTLA途径的分子缺陷与体内模型相结合，以评估这一途径在淋巴瘤和白血病的发生和发展中的作用，为治疗操作这些途径提供理论基础。

DESCRIPTION (provided by applicant): Emerging evidence indicates that immune and inflammatory cytokine pathways promote the development and progression of lymphoma, however the molecular mechanisms are poorly defined. The TNF receptor superfamily member, HVEM (herpesvirus entry mediator; TNFRSF14) and the Ig superfamily protein, BTLA (B and T lymphocyte attenuator) form a novel signaling network that regulates lymphocyte activation and proliferation. Importantly, recent genetic analyses of human lymphomas and related hematologic malignancies revealed frequent somatic mutations in HVEM and BTLA that are associated with poor prognosis. Our research provides new evidence that somatic point mutations in HVEM identified in human lymphomas specifically alter ligand engagement, potentially affecting intrinsic NFκB survival pathways and immune regulatory mechanisms. We identified a novel transcriptional regulatory pathway that down modulates BTLA that may account for the suppression of BTLA expression in B and T-lymphoma cells. The HVEM-BTLA pathway, although well-recognized in host defense, is poorly defined in the context of cancer. The proliferation inhibiting functions and frequent somatic mutations suggest that the HVEM-BTLA pathway may serve as a check-point for the development and progression of hematologic malignancies. In this project, the molecular mechanisms of the dysregulation of the HVEM and BTLA pathway in human lymphoma lines will be determined. The affect of the HVEM-BTLA pathway is examined in mouse models of B cell malignancies. An array of antibody and receptor-based agonists and antagonists of the HVEM-BTLA related cytokines have been developed, and mice with null and conditional gene deletions in HVEM and BTLA are available to complement the results in human lymphoma cells. Together, these aims integrate molecular defects in the HVEM-BTLA pathways in human lymphoma with in vivo models to evaluate this pathway in the development and progression of lymphoma and leukemia, providing the rationale to therapeutically manipulate these pathways.