Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone

Nicole A Kohart; Said M Elshafae; Wachirapan Supsahvad; Aylin Alasonyalilar-Demirer; Amanda R Panfil; Jingyu Xiang; Wessel P Dirksen; Deborah J Veis; Patrick L Green; Katherine N Weilbaecher; Thomas J Rosol

doi:10.1016/j.jbo.2019.100257

Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone

J Bone Oncol. 2019 Aug 20:19:100257. doi: 10.1016/j.jbo.2019.100257. eCollection 2019 Dec.

Authors

Nicole A Kohart¹, Said M Elshafae^{1

2

3}, Wachirapan Supsahvad^{1

4}, Aylin Alasonyalilar-Demirer^{1

5}, Amanda R Panfil¹, Jingyu Xiang⁶, Wessel P Dirksen¹, Deborah J Veis⁶, Patrick L Green¹, Katherine N Weilbaecher⁶, Thomas J Rosol^{1

7}

Affiliations

¹ Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.
² Department of Radiology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
³ Department of Pathology, Faculty of Veterinary Medicine, Benha University, Kalyubia 3736, Egypt.
⁴ Department of Pathology, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, Thailand.
⁵ Department of Pathology, Faculty of Veterinary Medicine, Bursa Uludag University, 16059 Bursa, Turkey.
⁶ Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁷ Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, 225 Irvine Hall, Athens, OH 45701, USA.

Abstract

Adult T-cell leukemia/lymphoma has a unique relationship to bone including latency in the marrow, and development of bone invasion, osteolytic tumors and humoral hypercalcemia of malignancy. To study these conditions, we established and characterized a novel mouse model of ATL bone metastasis. Patient-derived ATL cell lines including three that do not express HTLV-1 oncoprotein Tax (ATL-ED, RV-ATL, TL-Om1), an in vitro transformed human T-cell line with high Tax expression (HT-1RV), and an HTLV-1 negative T-cell lymphoma (Jurkat) were injected intratibially into NSG mice, and were capable of proliferating and modifying the bone microenvironment. Radiography, μCT, histopathology, immunohistochemistry, plasma calcium concentrations, and qRT-PCR for several tumor-bone signaling mRNAs were performed. Luciferase-positive ATL-ED bone tumors allowed for in vivo imaging and visualization of bone tumor growth and metastasis over time. ATL-ED and HT-1RV cells caused mixed osteolytic/osteoblastic bone tumors, TL-Om1 cells exhibited minimal bone involvement and aggressive local invasion into the adjacent soft tissues, Jurkat cells proliferated within bone marrow and induced minimal bone cell response, and RV-ATL cells caused marked osteolysis. This mouse model revealed important mechanisms of human ATL bone neoplasms and will be useful to investigate biological interactions, potential therapeutic targets, and new bone-targeted agents for the prevention of ATL metastases to bone.

Keywords: ATL, adult T-cell leukemia/lymphoma; Bone resorption; HHM, humoral hypercalcemia of malignancy; HTLV-1; HTLV-1, Human T-cell leukemia virus type 1; Hbz, HTLV-1 basic zipper protein; Lymphoma; Metastasis; Mouse model; NK, natural killer; NOD, non-obese diabetic; NSG, NOD-scid IL2Rgammanull; SCID, CB17-Prkdcscid; Tax, transcriptional activator from the X region; qRT-PCR, quantitative real-time polymerase chain reaction; μCT, micro-computed tomography.

Abstract

Grants and funding