title: Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells.
abstract: 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-related 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 kappaB (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.
authors.affiliation: Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Kisato
authors.initials: K
authors.lastname: Nosaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Sakai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000328:Adult; D000368:Aged; D001862:Bone Resorption / Q000097:blood / Q000209:etiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology* / Q000503:physiopathology; D016130:Immunophenotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000097:blood*; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010010:Osteoclasts / Q000473:pathology*; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor