In vivo tumorigenesis, osteolytic sarcomas, and tumorigenic cell lines from transgenic mice expressing the human T-lymphotropic virus type 1 (HTLV-1) Tax viral oncogene

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia, a disease commonly associated with hypercalcemia and osteolysis. There is no effective treatment and the osteolytic mechanisms are not fully understood. A mouse expressing the HTLV-1 oncogene Tax driven by the human granzyme B promoter (Tax+) develops osteolytic tumors. To investigate the development and progression of the bone-invasive malignancies, wild-type (WT), Tax+, and Tax+/Interferon(IFN)-γ-/- mice were evaluated over time by necropsy, histology, immunohistochemistry (IHC), flow cytometry, and advanced imaging. Tax+ and Tax+/IFN-γ-/- ear, tail, and feet malignancies consisted of poorly differentiated round to spindle-shaped cells with prominent neutrophilic infiltrates. Tail tumors originated from muscle, nerve, and/or tendon sheaths with frequent invasion into adjacent bone. F4/80+ and Mac-1+ histiocytic cells predominated within the tumors. We also created three Tax+/IFN-γ-/- cell lines for in vivo allografts and in vitro gene expression and bone resorption assays. Two cell lines were monocyte/macrophage in origin and all three formed tumors in vivo. Differences in Pthrp, Il-6, Il-1α and β, and G-csf gene expression in vitro correlated with differences in in vivo plasma calcium levels, tumor growth, metastasis, and neutrophilic inflammation. Tax+ mouse tumors were diagnosed as bone-invasive histiocytic sarcomas. Their cell lines are ideal for further examination of HTLV-1 Tax's role in osteolytic tumor formation and the development of hypercalcemia and tumor-associated inflammation.