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Blood, 15 January 2002, Vol. 99, No. 2, pp. 634-640
NEOPLASIA
Mechanism of hypercalcemia in adult T-cell leukemia:
overexpression of receptor activator of nuclear factor  B ligand on
adult T-cell leukemia cells
Kisato Nosaka,
Takeshi Miyamoto,
Tatsunori Sakai,
Hiroaki Mitsuya,
Toshio Suda, and
Masao Matsuoka
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.
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
 B (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.
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