HVEM-BTLA Pathway in Lymphoma

描述（由申请人提供）：新的证据表明免疫和炎症细胞因子途径促进淋巴瘤的发生和进展，但分子机制尚不明确。TNF受体超家族成员HVEM（疱疹病毒进入介体; TNFRSF 14）和IG超家族蛋白BTLA（B和T淋巴细胞衰减剂）形成调节淋巴细胞活化和增殖的新型信号传导网络。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揭示了HVEM和BTLA中与不良预后相关的频繁体细胞突变。我们的研究提供了新的证据，即在人类淋巴瘤中鉴定的HVEM中的体细胞点突变特异性地改变配体结合，潜在地影响内在NFκB存活途径和免疫调节机制。我们鉴定了一种新的下调BTLA的转录调节途径，这可能是抑制B和T淋巴瘤细胞中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可，但在癌症的背景下定义得很差。HVEM-BTLA通路的增殖抑制功能和频繁的体细胞突变提示HVEM-BTLA通路可能是恶性血液病发生和发展的一个检查点。在这个项目中，HVEM和BTLA通路在人类淋巴瘤细胞系失调的分子机制将被确定。在B细胞恶性肿瘤的小鼠模型中检查HVEM-BTLA途径的影响。已经开发了一系列HVEM-BTLA相关细胞因子的基于抗体和受体的激动剂和拮抗剂，并且在HVEM和BTLA中具有无效和条件性基因缺失的小鼠可用于补充人淋巴瘤细胞中的结果。总之，这些目标将人类淋巴瘤中HVEM-BTLA途径中的分子缺陷与体内模型相结合，以评估该途径在淋巴瘤和白血病的发展和进展中的作用，为治疗性操纵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.