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

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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.

Original languageEnglish
Article number100257
JournalJournal of Bone Oncology
Volume19
DOIs
StatePublished - Dec 2019

Keywords

  • Bone resorption
  • HTLV-1
  • Lymphoma
  • Metastasis
  • Mouse model

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    Kohart, N. A., Elshafae, S. M., Supsahvad, W., Alasonyalilar-Demirer, A., Panfil, A. R., Xiang, J., Dirksen, W. P., Veis, D. J., Green, P. L., Weilbaecher, K. N., & Rosol, T. J. (2019). Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone. Journal of Bone Oncology, 19, [100257]. https://doi.org/10.1016/j.jbo.2019.100257