Priority Research Papers:

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice

Alison K. Esser, Daniel A. Rauch, Jingyu Xiang, John C. Harding, Nicole A. Kohart, Michael H. Ross, Xinming Su, Kevin Wu, Devra Huey, Yalin Xu, Kiran Vij, Patrick L. Green, Thomas J. Rosol, Stefan Niewiesk, Lee Ratner and Katherine N. Weilbaecher _

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Oncotarget. 2017; 8:69250-69263. https://doi.org/10.18632/oncotarget.20565

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Alison K. Esser1,*, Daniel A. Rauch1,*, Jingyu Xiang1, John C. Harding1, Nicole A. Kohart2, Michael H. Ross1, Xinming Su1, Kevin Wu1, Devra Huey2, Yalin Xu1, Kiran Vij1, Patrick L. Green2, Thomas J. Rosol2, Stefan Niewiesk2, Lee Ratner1 and Katherine N. Weilbaecher1

1 Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA

2 Department of Veterinary Biosciences, School of Veterinary Medicine, The Ohio State University, Columbus, OH, USA

* Co-authors

Correspondence to:

Katherine N. Weilbaecher, email:

Keywords: HTLV-1, ATL, leukemia, HBZ, bone

Received: June 10, 2017 Accepted: August 03, 2017 Published: August 27, 2017


Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced osteolytic bone loss is unknown. To determine if HBZ is sufficient for the development of bone loss, we established a transgenic Granzyme B HBZ (Gzmb-HBZ) mouse model. Lymphoproliferative disease including tumors, enlarged spleens and/or abnormal white cell counts developed in two-thirds of Gzmb-HBZ mice at 18 months. HBZ positive cells were detected in tumors, spleen and bone marrow. Importantly, pathologic bone loss and hypercalcemia were present at 18 months. Bone-acting factors were present in serum and RANKL, PTHrP and DKK1, key mediators of hypercalcemia and bone loss, were upregulated in Gzmb-HBZ T cells. These data demonstrate that Gzmb-HBZ mice model ATL bone disease and express factors that are current therapeutic targets for metastatic and bone resident tumors.

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