MECHANISMS OF BONE-LESIONS IN MULTIPLE-MYELOMA AND LYMPHOMA

BACKGROUND. Bone lesions and hypercalcemia occur rarely in patients wi th hematologic malignancies, except those patients with multiple myelo ma and adult T-cell leukemia/lymphoma (ATL) associated with the human T-cell leukemia/lymphoma virus-1 (HTLV-1) virus. The primary mechanism for bone destruction in patients with myeloma and lymphoma is increas ed osteoclastic bone resorption. In patients with multiple myeloma, ne w bone formation is also inhibited. Mediators including lymphotoxin, i nterleukin-1 beta, parathyroid hormone related protein (PTHrP), and in terleukin-6, produced by the myeloma cells or by marrow stromal cells in response to myeloma cells, have been implicated as osteoclast-activ ating factors (OAF) in multiple myeloma. However, most studies to iden tify OAF produced by myeloma cells have been inconclusive. METHODS. To try to identify the OAF produced by myeloma cells, we developed an in vivo model of human myeloma bone disease using the ARH-77 myeloma cel l line transplanted into severe combined immunodeficiency mice. RESULT S. We found that a novel cytokine(s) may be responsible for bone destr uction. Interleukin-1 and PTHrP mediate bone destruction in patients w ith ATL. These factors can be detected in media conditioned by ATL cel ls or by lymphocytes infected with HTLV-1. Furthermore, serum PTHrP le vels are increased in ATL patients. In patients with Hodgkin's disease or other types of non-Hodgkin's lymphoma, 1,25-(OH)(2)D-3 or PTHrP is produced by the lymphoma cells and mediates bone destruction. Chemoth erapy or resection of the lymphoma decreases 1,25-(OH)2D(3) levels and hypercalcemia in these patients. CONCLUSION. Thus, OAF produced local ly by the tumor or the marrow microenvironment play an important role in the bone destruction seen in patients with hematologic malignancies . (C) 1997 American Cancer Society.