Clinical issue

Multiple myeloma is a hematological malignancy that affects approximately 100,000 patients in the USA, with nearly 20,000 new cases diagnosed each year. Myeloma is characterized by the clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. Despite many advances in the treatment of multiple myeloma, it remains an incurable and fatal malignancy. Myeloma progression and the development of osteolytic bone disease are linked inextricably and depend on cellular interactions within the bone marrow microenvironment. Understanding the bone marrow microenvironment in myeloma is crucial to elucidate the mechanisms involved in disease progression and to identify novel therapeutic targets.

Results

In this study, the authors describe a new murine model of myeloma in which the host microenvironment can be modified genetically. They induced myeloma by inoculating myeloma cells into mice with compromised B- and T-cell development that results from their lack of recombination activating gene 2 (RAG-2). Myeloma-bearing RAG-2−/− mice exhibit tumor growth within the bone marrow and develop osteolytic bone disease. These features are consistent with both human myeloma and an original Radl 5T model for the disease, suggesting that these mice accurately model myeloma. RAG2−/− mice are easily bred with other genetically modified mice to generate myeloma models with genetic modifications to the host microenvironment. The authors use this mouse model to show that deletion of host matrix metalloproteinase 9 reduces the tumor burden and osteolytic bone disease that are associated with myeloma.

Implications and future directions

A major limitation of the current murine models of myeloma is that manipulation of the bone marrow microenvironment, independent of the tumor, is limited to systemic pharmacological reagents. The establishment of myeloma in RAG-2−/− mice permits molecular examination of the host contribution to myeloma pathogenesis in vivo. This sophisticated model should allow for investigation of important questions in myeloma research regarding the relative contribution of host-derived versus tumor-derived factors.