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Models, Mechanisms, and Treatment of Adult T-cell Leukemia/Lymphoma Bone Metastasis

Kohart, Nicole Ann, Kohart
http://rave.ohiolink.edu/etdc/view?acc_num=osu1503248777003095

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Adult T-cell Leukemia/Lymphoma (ATL) is a rapidly fatal hematological malignancy that develops in a subset of Human T-cell Leukemia Virus Type 1 (HTLV-1) carriers after a 20-40 year latency. ATL has a unique relationship to bone characterized by aggressive bone invasion, long latency in the marrow, osteolytic bone metastasis, and hypercalcemia of malignancy. ATL bone metastasis and paraneoplastic syndromes cause substantial patient morbidity and a poor prognosis of less than a year. Novel therapeutic approaches for ATL are imperative to improve patient quality of life and prognosis. Therapies targeting both tumor and the bone microenvironment have been investigated in other bone tropic tumors but largely remain unstudied in ATL bone metastasis. This is due to the lack of understanding the mechanisms of the ATL tumor-bone communication and the paucity of appropriate animal models to study this focus of the disease. Several animal models exist to study the pathogenesis of HTLV-1 and ATL; however, models to recapitulate and describe the intimate tumor-bone interaction have not been well described. In this study, we developed and characterized novel xenograft mouse models of ATL bone metastasis. We introduced primary and in vitro HTLV-1 transformed cell lines into the tibias of immunosuppressed mice. Mice developed aggressive bone tumors and distant metastasis within 4 weeks. Tumor-bone phenotypes of xenograft mice ranged from minimal bone changes, mixed osteolytic/osteoblastic lesions, to marked osteolytic phenotypes similar to what is seen in clinical patients. The RVATL xenograft model with the greatest degree of tumor-associated osteolysis had significantly higher mRNA expression of parathyroid hormone-related protein (PTHrP), suggesting a significant paracrine role for PTHrP in ATL bone metastasis. Knockdown of PTHrP in an ATL cell line significantly decreased tumor growth and associated osteolysis in vivo. These models mimic key aspects of ATL in bone and will be useful for preclinical and pathogenesis studies of ATL bone metastasis. Elevated levels of bone acting factors PTHrP, interleukin-6 (IL-6), and macrophage inflammatory protein-1a (MIP-1a) are found in serum of patients with ATL. Studies have defined an endocrine role for these factors to act on osteoclasts at distant sites to promote widespread bone resorption and hypercalcemia; however, the paracrine role they play in the ATL-bone communication remains elusive. We investigated the paracrine role of osteolytic factors PTHrP, MIP-1a, and autotaxin in bone lymphoma through overexpressing each in a leukemic T-cell line, Jurkat that does not normally express these factors. PTHrP overexpression resulted in marked pathologic osteolysis in vivo and significant bone loss in ex vivo calvarial assays. These findings showed a sufficient and significant paracrine role for PTHrP in pathologic osteolysis in T-cell lymphoma bone metastasis. In addition, this report describes a novel tool that will be useful to dissect the critical factors in bone lymphoma that are responsible for adapting the bone microenvironment to promote tumorigenesis and bone metastasis. To investigate new treatments for ATL bone metastases, we selected two agents that have demonstrated success in other bone-tropic neoplasms but have not been evaluated in ATL. Histone deacetylase inhibitors (HDACi) are a class of anti-cancer agents that cease tumor growth, and stimulate tumor-cell apoptosis. Zoledronic acid (Zol) is a third-generation bisphosphonate that inhibits osteoclasts and has anti-tumor effects. We found that Zoledronic acid and HDACi, AR-42 significantly decreased cell viability in vitro and Zol decreased tumor-associated osteolysis and tumor burden in vivo. Our results support the use of Zol as a potent adjuvant therapy to reduce tumor burden in bone and associated osteolysis. In this dissertation research, we established and characterized novel mouse models of ATL bone metastasis for preclinical and pathogenesis studies of ATL. We found several bone-acting factors expressed in ATL bone tumors, notably high PTHrP expression found in the osteolytic RVATL model. We further studied the important paracrine role of PTHrP in bone lymphoma using in vivo, in vitro, and ex vivo techniques. Finally, we investigated the potential of a tumor-bone targeted therapeutic approach using a novel mouse model of ATL in bone that we had developed. The novel tools and data generated in this research dissertation extends our current knowledge of the pathogenesis of ATL bone metastasis and the tumor-bone communication and provides a platform for future directions in the study of this important disease.
Thomas Rosol, DVM, PhD (Committee Member)
Maxey Wellman, DVM, PhD (Committee Member)
Beth Lee, PhD (Committee Member)
Toribio Ramiro, DVM, PhD (Committee Member)
220 p.
Comparative; Pathology
Adult T cell Leukemia Lymphoma; bone metastasis

Recommended Citations

Citations

  • Kohart, Kohart, N. A. (2017). Models, Mechanisms, and Treatment of Adult T-cell Leukemia/Lymphoma Bone Metastasis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1503248777003095

    APA Style (7th edition)

  • Kohart, Kohart, Nicole. Models, Mechanisms, and Treatment of Adult T-cell Leukemia/Lymphoma Bone Metastasis . 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1503248777003095.

    MLA Style (8th edition)

  • Kohart, Kohart, Nicole. "Models, Mechanisms, and Treatment of Adult T-cell Leukemia/Lymphoma Bone Metastasis ." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1503248777003095

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.