Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor κB 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

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…In other physiopathological conditions, like arthritis, activated T cells regulate bone loss via the expression of RANKL (Kong et al, 1999, Kotake et al, 2001). This is not the only RANKL related mediation by T lymphocytes, of course, as it is known to signal for gene transcription in the T-cells themselves, and has been identified as crucial for the mechanism of hypercalcaemia in some T-cell leukemia (Nosaka et al, 2002). These observations led to a study showing that myeloma plasma cells upregulate RANKL expression and secretion in both activated and autologous T cells (Giuliani et al, 2002).…”

Endocrine and metabolic disorders in HTLV-1 infected patients

“…[16][17] In 70%-80% of the acute ATLL form, the patients develop the humoral hypercalcemia of malignancy (HHM), a paraneoplastic syndrome characterized by hypercalcemia, osteoporosis and osteolytic lesions. [13][14][15]18,19 This suggests that there should be released or expressed molecules in ATLL cells performing a crucial role in HHM etiology. 20 The HHM of patients with acute ATLL is caused by mechanisms that act synergistically, affecting directly or indirectly the osteoclastic differentiation.…”

“…24 Nosaka et al suggest that the decrease in the production of OPG in patients with ATTL can be one of the pathogenic mechanisms of the hypercalcemia. 18 …”

“…17 As the PTHrP is not able to induce the differentiation of the precursor hematopoietic cells into osteoclasts and an association between their elevated serum levels and HHM is not always observed, this indicates that other mechanisms contribute to this process. 18 …”

“…21 Patients with ATLL and hypercalcemia present increase of the expression of RANK. 14,18 Thus, the invasion of the bone marrow by ATLL cells expressing RANKL in its surface induces osteoclastic differentiation causing hypercalcemia.…”