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 NF?B 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.

Public Health Relevance

This project examines how cellular communication proteins called cytokines that normally control the growth of white blood cells change when their genes are mutated in lymphoma and leukemia. The experiments here will determine whether potential drugs directed at these cytokines halt the growth of lymphoma and leukemia.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Correa, Ricardo G; Krajewska, Maryla; Ware, Carl F et al. (2014) The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling. Oncotarget 5:1666-82
Gommerman, Jennifer L; Browning, Jeffrey L; Ware, Carl F (2014) The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity. Cytokine Growth Factor Rev 25:139-45
Bjordahl, Ryan L; Steidl, Christian; Gascoyne, Randy D et al. (2013) Lymphotoxin network pathways shape the tumor microenvironment. Curr Opin Immunol 25:222-9
Sedy, John R; Bjordahl, Ryan L; Bekiaris, Vasileios et al. (2013) CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells. J Immunol 191:828-36
Bekiaris, Vasileios; Sedy, John R; Rossetti, Maura et al. (2013) Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-** and are elevated in rheumatoid arthritis. J Immunol 191:4611-8
Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68
Bekiaris, Vasileios; Sedý, John R; Macauley, Matthew G et al. (2013) The inhibitory receptor BTLA controls ?? T cell homeostasis and inflammatory responses. Immunity 39:1082-94