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

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; ... (2019). HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia. JCI insight, 4(19) JCI Insight 10.1172/jci.insight.128713

[img] Text
jciinsight-4-128713.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (7MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Rauch, Daniel


600 Technology > 610 Medicine & health




JCI Insight




Rebeka Gerber

Date Deposited:

07 Jan 2020 08:46

Last Modified:

07 Jan 2020 08:46

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Bone Biology Bone disease Oncogenes Oncology




Actions (login required)

Edit item Edit item
Provide Feedback