HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia

Jingyu Xiang, Daniel A. Rauch, Devra D. Huey, Amanda R. Panfil, Xiaogang Cheng, Alison K. Esser, Xinming Su, John C. Harding, Yalin Xu, Gregory C. Fox, Francesca Fontana, Takayuki Kobayashi, Junyi Su, Hemalatha Sundaramoorthi, Wing Hing Wong, Yizhen Jia, Thomas J. Rosol, Deborah J. Veis, Patrick L. Green, Stefan NiewieskLee Ratner, Katherine N. Weilbaecher

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numbere128713
JournalJCI Insight
Volume4
Issue number19
DOIs
StatePublished - Jan 1 2019

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    Xiang, J., Rauch, D. A., Huey, D. D., Panfil, A. R., Cheng, X., Esser, A. K., Su, X., Harding, J. C., Xu, Y., Fox, G. C., Fontana, F., Kobayashi, T., Su, J., Sundaramoorthi, H., Wong, W. H., Jia, Y., Rosol, T. J., Veis, D. J., Green, P. L., ... Weilbaecher, K. N. (2019). HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia. JCI Insight, 4(19), [e128713]. https://doi.org/10.1172/jci.insight.128713