Macrophage inflammatory protein-1alpha induces hypercalcemia in adult T-cell leukemia

Hypercalcemia is observed in >80% of ATL. Serum MIP-1alpha levels were elevated in all 24 ATL with hypercalcemia but undetectable in all 10 patients with humoral hypercalcemia of malignancy with solid tumors and in 34 of 37 ATL without hypercalcemia. We propose that serum MIP-1alpha is a clinical hallmark for hypercalcemia in ATL.

High serum cytokines levels are not always associated with hypercalcemia in patients with adult T-cell leukemia (ATL), suggesting that other factors are involved in the pathogenesis of ATL patients with hypercalcemia. This study was designed to determine the role of macrophage inflammatory protein-1alpha (MIP-1alpha), a chemokine recently described as an osteoclast stimulatory factor, in ATL-associated hypercalcemia.

We measured serum interleukin (IL)-1beta, IL-6, TNF-alpha, parathyroid hormone-related protein (PTHrP), and MIP-1alpha levels in ATL patients by enzyme-linked immunosorbent assays. FACScan was used to measure the expression of RANKL on ATL cells. Osteoclast formation in cocultures of ATL cells and peripheral blood mononuclear cells (PBMCs) was evaluated by TRACP staining.

High serum MIP-1alpha levels were noted in all 24 ATL patients with hypercalcemia and in 3 of 37 ATL patients without hypercalcemia. The elevated levels of MIP-1alpha and calcium in ATL patients decreased after effective chemotherapy, emphasizing the role of MIP-1alpha in ATL hypercalcemia. ATL cells spontaneously produced MIP-1alpha. MIP-1alpha significantly enhanced human monocyte (precursor cells of osteoclasts) migration and induced RANKL expression on ATL cells. ATL cell-induced osteoclast formation from PBMCs was inhibited by anti-MIP-1alpha antibody and osteoprotegerin.

Our results suggest that MIP-1alpha can induce RANKL on ATL cells in autocrine fashion and that RANKL seems to mediate the hypercalcemic effect of MIP-1alpha in ATL. We propose that MIP-1alpha is the clinical hallmark of hypercalcemia in ATL and could be a potentially useful therapeutic target.