{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:16:36Z","timestamp":1791353796282,"version":"4.3.1"},"reference-count":36,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hypercalcemia is one of the most frequent and serious complications in patients with adult T-cell leukemia (ATL) and is due to marked bone resorption by accumulation of osteoclasts (OCLs). Although several cytokines such as interleukin 1 and parathyroid hormone\u2013related protein are thought to be involved in the development of high serum Ca++ levels, its precise underlying mechanism remains unknown. This study analyzed the expression of various genes that are thought to regulate serum Ca++ levels in ATL and showed that the overexpression of the receptor activator of nuclear factor \u03baB (RANK) ligand gene correlated with hypercalcemia. ATL cells from patients with hypercalcemia, which highly expressed the transcripts of the RANK ligand (RANKL) gene, induced the differentiation of human hematopoietic precursor cells (HPCs) into OCLs in vitro in the presence of macrophage colony-stimulating factor (M-CSF). In contrast, ATL cells from patients without hypercalcemia did not induce such differentiation, suggesting that the induction of the differentiation correlated with the expression of the RANKL gene in ATL cells. Cell differentiation was suppressed by osteoprotegerin\/Fc, an inhibitor of RANKL, indicating that such differentiation occurred through the RANK-RANKL pathway. In addition, direct contact between ATL cells and HPCs was essential for the differentiation, suggesting that not the soluble form but membrane-bound RANKL played a role in this process. These results strongly suggested that ATL cells induce the differentiation of HPCs to OCLs through RANKL expressed on their surface, in cooperation with M-CSF, and ultimately cause hypercalcemia.<\/jats:p>","DOI":"10.1182\/blood.v99.2.634","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T08:46:47Z","timestamp":1027759607000},"page":"634-640","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":136,"title":["Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor \u03baB ligand on adult T-cell leukemia cells"],"prefix":"10.1182","volume":"99","author":[{"given":"Kisato","family":"Nosaka","sequence":"first","affiliation":[{"name":"From the Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine II and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"From the Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine II and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsunori","family":"Sakai","sequence":"additional","affiliation":[{"name":"From the Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine II and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[{"name":"From the Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine II and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Suda","sequence":"additional","affiliation":[{"name":"From the Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine II and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"From the Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine II and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021218145043200_B1","first-page":"73","article-title":"Adult T cell leukemia in Japan.","volume-title":"Topics in Hematology, the 16th International Congress of Hematology.","author":"Takatsuki","year":"1977"},{"key":"2020021218145043200_B2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1182\/blood.V50.3.481.481","article-title":"Adult T-cell leukemia: clinical and hematologic features of 16 cases.","volume":"50","author":"Uchiyama","year":"1977","journal-title":"Blood."},{"key":"2020021218145043200_B3","doi-asserted-by":"crossref","first-page":"7415","DOI":"10.1073\/pnas.77.12.7415","article-title":"Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.","volume":"77","author":"Poiesz","year":"1980","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218145043200_B4","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1073\/pnas.78.10.6476","article-title":"Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera.","volume":"78","author":"Hinuma","year":"1981","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218145043200_B5","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1073\/pnas.79.6.2031","article-title":"Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease.","volume":"79","author":"Yoshida","year":"1982","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218145043200_B6","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/317395a0","article-title":"Human T-lymphotropic retroviruses.","volume":"317","author":"Wong-Staal","year":"1985","journal-title":"Nature."},{"key":"2020021218145043200_B7","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.1182\/blood.V86.10.3619.bloodjournal86103619","article-title":"Molecular mechanisms of human T-cell leukemia\/lymphotropic virus type I infection.","volume":"86","author":"Franchini","year":"1995","journal-title":"Blood."},{"key":"2020021218145043200_B8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1385\/1-59259-024-1:211","article-title":"Adult T-cell leukemia\/lymphoma.","volume-title":"Infectious Causes of Cancer.","author":"Matsuoka","year":"2000"},{"key":"2020021218145043200_B9","first-page":"221","article-title":"Chemotherapy of ATL.","volume-title":"Adult T-cell Leukemia. 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