HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia
Copyright: © 2019, American Society for Clinical Investigation. Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models. Humanized mice infected with HTLV-1 developed lymphoproliferative disease and continuous, progressive osteolytic bone lesions. HTLV-1 lacking HBZ displayed only modest delays to lymphoproliferative disease but significantly decreased disease-associated bone loss compared with HTLV-1–infected mice. Gene expression array of acute ATL patient samples demonstrated increased expression of RANKL, a critical regulator of osteoclasts. We found that HBZ regulated RANKL in a c-Fos–dependent manner. Treatment of HTLV-1–infected humanized mice with denosumab, a monoclonal antibody against human RANKL, alleviated bone loss. Using patient-derived xenografts from primary human ATL cells to induce lymphoproliferative disease, we also observed profound tumor-induced bone destruction and increased c-Fos and RANKL gene expression. Together, these data show the critical role of HBZ in driving ATL-associated bone loss through RANKL and identify denosumab as a potential treatment to prevent bone complications in ATL patients.
Xiang, Jingyu; Rauch, Daniel A.; Huey, Devra D.; Panfil, Amanda R.; Cheng, Xiaogang; Esser, Alison K.; Su, Xinming; Harding, John C.; Xu, Yalin; Fox, Gregory C.; Fontana, Francesca; Kobayashi, Takayuki; Su, Junyi; Sundaramoorthi, Hemalatha; Wong, Wing Hing; Jia, Yizhen; Rosol, Thomas J.; Veis, Deborah J.; Green, Patrick L.; Niewiesk, Stefan; Ratner, Lee; and Weilbaecher, Katherine N., "HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia" (2019). Biomedical Sciences Open Access Publications. 118.