TY - JOUR
T1 - Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone
AU - Kohart, Nicole A.
AU - Elshafae, Said M.
AU - Supsahvad, Wachirapan
AU - Alasonyalilar-Demirer, Aylin
AU - Panfil, Amanda R.
AU - Xiang, Jingyu
AU - Dirksen, Wessel P.
AU - Veis, Deborah J.
AU - Green, Patrick L.
AU - Weilbaecher, Katherine N.
AU - Rosol, Thomas J.
N1 - Funding Information:
This work was funded through grants from the National Cancer Institute ( P01 CA100730 to TJR, KNW and PLG) and ( T32 OD010429 to NAK). Animal research reported in this publication was supported by the Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number P30 CA016058 . We thank the Target Validation Shared Resource (TVSR) at the Ohio State University Comprehensive Cancer Center for providing the NSG mice used in the preclinical studies described herein. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. We thank Alan Flechtner and Anne Saulsbery for tissue processing and preparation of slides. We thank Lianbo Yu form the OSU Center for Biostatistics and Bioinformatics for his assistance with some of the statistics. Finally, we thank our medical illustrator Tim Vojt for his invaluable assistance in creating all the figures.
Funding Information:
This work was funded through grants from the National Cancer Institute (P01 CA100730 to TJR, KNW and PLG) and (T32 OD010429 to NAK). Animal research reported in this publication was supported by the Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number P30 CA016058. We thank the Target Validation Shared Resource (TVSR) at the Ohio State University Comprehensive Cancer Center for providing the NSG mice used in the preclinical studies described herein. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. We thank Alan Flechtner and Anne Saulsbery for tissue processing and preparation of slides. We thank Lianbo Yu form the OSU Center for Biostatistics and Bioinformatics for his assistance with some of the statistics. Finally, we thank our medical illustrator Tim Vojt for his invaluable assistance in creating all the figures.
Publisher Copyright:
© 2019 The Authors
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - Bone resorption
KW - HTLV-1
KW - Lymphoma
KW - Metastasis
KW - Mouse model
UR - http://www.scopus.com/inward/record.url?scp=85074028945&partnerID=8YFLogxK
U2 - 10.1016/j.jbo.2019.100257
DO - 10.1016/j.jbo.2019.100257
M3 - Article
C2 - 31871882
AN - SCOPUS:85074028945
SN - 2212-1374
VL - 19
JO - Journal of Bone Oncology
JF - Journal of Bone Oncology
M1 - 100257
ER -