1. HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice
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Nicole A. Kohart, Daniel Rauch, Alison K. Esser, Jingyu Xiang, Devra Huey, Patrick L. Green, Kiran Vij, Kevin Wu, Xinming Su, Thomas J. Rosol, Lee Ratner, John C. S. Harding, Stefan Niewiesk, Yalin Xu, Michael H. Ross, and Katherine N. Weilbaecher
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0301 basic medicine ,Osteolysis ,Bone disease ,T cell ,bone ,03 medical and health sciences ,0302 clinical medicine ,HBZ ,hemic and lymphatic diseases ,Medicine ,biology ,business.industry ,leukemia ,Wnt signaling pathway ,medicine.disease ,3. Good health ,Lymphoma ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,HTLV-1 ,ATL ,RANKL ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Bone marrow ,business ,Priority Research Paper - Abstract
// Alison K. Esser 1,* , Daniel A. Rauch 1,* , Jingyu Xiang 1 , John C. Harding 1 , Nicole A. Kohart 2 , Michael H. Ross 1 , Xinming Su 1 , Kevin Wu 1 , Devra Huey 2 , Yalin Xu 1 , Kiran Vij 1 , Patrick L. Green 2 , Thomas J. Rosol 2 , Stefan Niewiesk 2 , Lee Ratner 1 and Katherine N. Weilbaecher 1 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 Abstract 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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- 2017