Fig. (2) Humoral hypercalcemia of malignancy (HHM) in ATL is caused by increased osteoclastic bone resorption. Cancer cells secrete bone regulatory factors, including parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein-1 alpha (MIP-1α), calcitriol (1,25(OH)₂D), and receptor activator of nuclear kappa-B ligand (RANKL) to increase osteoclast activity. The resorbing bone secretes bone-derived growth factors that increase ATL cell growth. In osteoblasts, the RANKL/OPG expression ratio increases when cells are co-cultured with T-cell leukemia lines. Antibodies against HTLV-1 Gp46 can inhibit osteoprotegerin (OPG) and contributes to the pathogenesis of hypercalcemia.