1989 Fiscal Year Final Research Report Summary
Hypercalcemic Factors in ATL
| Project/Area Number |
62570537
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MOTOKURA Toru Fourth Department of Internal Medicine, University of Tokyo, School of Medicine, Instructor and Research Associate, 医学部(分), 助手 (00192823)
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| Co-Investigator(Kenkyū-buntansha) |
IGARASHI Tetsuya Fourth Department of Internal Medicine, University of Tokyo, School of Medicine,, 医学部(分), 講師 (00134601)
MATSUMOTO Toshio Fourth Department of Internal Medicine, University of Tokyo, School of Medicine,, 医学部(分), 講師 (20157374)
WATANABE Toshiki Department of Viral Oncology, Cancer Institute, Research Associate, ウイルス腫瘍部, 研究員 (30182934)
TAKAHASHI Shunji Fourth Department of Internal Medicine, University of Tokyo, School of Medicine,, 医学部(分), 助手
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| Project Period (FY) |
1987 – 1989
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| Keywords | adult T-cell leukemia-lymphoma / hypercalcemia / parathyroid hormone-related protein |
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| Research Abstract |
Hypercalcemia frequently develops in patients with adult T-cell leukemia-lymphoma (ATL). Clinical features of calcium metabolism in ATL are very similar to those in humoral hypercalcemia of malignancy (HHM) associated with elaboration of parathyrold hormone-related protein (PTHrP) by solid tumors. In this project, we first examined the conditioned media of various hematopoietic cell lines for the presence of PTH-like activity. Among the cell lines tested, only HTLY-1-infected T- cell line, MT-2, secrete cyclic AMP production-stimulating activity in osteoblast-like UMR 106 cells that was completely inhibited by hPTH(3-34). According to RNA blot analysis with synthesized oligonucleotides hybridizable to the sequence of PTHrP, PTHrP mRNA was expressed in MT-2 cells. We next analyzed the clinical materials containing ATL cells from 3 patients for production of PTHrP. ATL cells synthesized PTHrP mRNA in vivo with much more abundance than MT-2 cells, and the extracellular fluids of these patients contained PTH-like activity that was chromatographically indistinguishable from those in solid tumors causing HHM and MT-2 cells. These results suggest that PTHrP plays an important role in development of hypercalcemia in ATL.
The treatment of 12-0-tetradecanoylphorbol 13-acetate(TPA) increased the steady-state level of PTHrP mRNA in MT-2 cells and the secretion of PTH-like activity from MT-2 cells as reported in. osteosarcoma cells. Among the normal lymphocytes of different origin tested, Tonsilar lymphocytes expressed PTHrP mRNA after TPA treatment, indicating that the effect of TPA on PTHrP expression is not specific to these cell lines. It is suggested that normal lymphocytes produce PTHrP in response to certain physiological stimuli and that ATL develops from a transformation of lymphocytes which can produce PTHrP.
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