HVEM-BTLA Pathway in Lymphoma

描述（由申请人提供）：新出现的证据表明免疫和炎症细胞因子通路促进淋巴瘤的发生和进展，但其分子机制尚不明确。TNF受体超家族成员HVEM（疱疹病毒进入介质；TNFRSF14）和Ig超家族蛋白BTLA （B和T淋巴细胞衰减剂）形成了一个调节淋巴细胞激活和增殖的新信号网络。重要的是，最近对人类淋巴瘤和相关血液恶性肿瘤的遗传分析显示，HVEM和BTLA中频繁的体细胞突变与预后不良有关。我们的研究提供了新的证据，证明在人类淋巴瘤中发现的HVEM的体细胞点突变特异性地改变配体接合，潜在地影响内在的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，下调BTLA，这可能是B和t淋巴瘤细胞中BTLA表达抑制的原因。HVEM-BTLA通路虽然在宿主防御中得到广泛认可，但在癌症背景下却定义不清。增殖抑制功能和频繁的体细胞突变提示HVEM-BTLA通路可能作为血液恶性肿瘤发生和进展的检查点。在本项目中，将确定HVEM和BTLA通路在人淋巴瘤系中失调的分子机制。HVEM-BTLA通路在B细胞恶性肿瘤小鼠模型中的作用。HVEM-BTLA相关细胞因子的一系列抗体和受体激动剂和拮抗剂已经被开发出来，HVEM和BTLA基因缺失和条件缺失的小鼠可以在人类淋巴瘤细胞中补充结果。总之，这些目标将人类淋巴瘤HVEM-BTLA通路中的分子缺陷与体内模型结合起来，以评估该通路在淋巴瘤和白血病的发生和进展中，为治疗性地操纵这些通路提供理论依据。

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.