Generation of a Novel, Multi-Stage, Progressive, and Transplantable Model of Multiple Myeloma

Abstract 327

Multiple myeloma is characterized by the progressive expansion of monoclonal plasma cells in the bone marrow, which leads to the production of serum and/or urine monoclonal proteins and systemic complications including lytic bone lesions, renal abnormalities hypercalcemia, and infections. Although the treatment of multiple myeloma has vastly improved, multiple myeloma remains a generally incurable disease. Transgenic mouse models have been generated that develop plasma cell accumulations or myeloma, however these models are quite imperfect in mimicking the human disease. Quite serendipitously, we have generated a multi-stage, progressive, and transplantable mouse model of multiple myeloma, crossing a genetically modified mouse with aberrant class switch recombination with another modified mouse that has elevated DNA damage response signaling. We have reported that cells expressing the hypermorphic Rad50^s allele show constitutive ATM activation, leading to cancer predisposition and aggressive hematopoietic failure in Rad50^s/s mice. While deficiency of the transcription factor Mef/Elf4, which regulates the quiescence of hematopoietic stem/progenitor cells, can mitigate hematopoietic failure observed in Rad50^s/s mice, we found that 70% of Mef^−/−Rad50^s/s mice more than 200 days old died from multiple myeloma, plasmacytoma, or plasma cell leukemia, confirmed by pathology, immunohistochemistry, flowcytometry (CD138/B220 profiles), and PCR analysis for VDJ recombination. Prior to the onset of the plasma cell neoplasms, the Mef^−/−Rad50^s/s mice show abnormal plasma cell accumulation in the peripheral blood and bone marrow, which worsens with age. As the mice age, they also develop progressive increases in g-globulin levels and decreases in serum albumin levels. Monoclonal protein peaks were frequently observed in the serum of mice older than 200 days, and in step with the progressive nature of these manifestations, anemia and lower bone mineral density becomes apparent as the mice further age. Overall, the median survival of the Mef^−/−Rad50^s/s mice is approximately 470 days. The plasma cell neoplasms derived from Mef^−/−Rad50^s/s mice can be transplanted into recipient mice and the onset of the transplanted disease is markedly accelerated, to approximately 4 weeks post transplantation. Thus, the transplanted neoplastic Mef^−/−Rad50^s/s plasma cells appear to be more aggressive than the original ones. Taken together, our findings suggest that the Mef^−/−Rad50^s/s animal model can recapitulate the spectrum and pace of human plasma cell neoplasms, including the progression from monoclonal gammopathy to multiple myeloma. Class switch recombination is facilitated in Mef^−/−Rad50^s/s B cells in vitro, compared with control, Mef^−/−, and Rad50^s/s B cells, thus the plasma cell neoplasms found in Mef^−/−Rad50^s/s mice may result from Rad50^s-driven oncogenesis. This novel Mef^−/−Rad50^s/s myeloma animal model should be useful for the drug screening of novel anti-myeloma compounds, as well as defining the pathogenesis of multiple myeloma/plasma cell neoplasms.