Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms.

Takashi Asai,Kazunori Murata,Stephen D Nimer,Delphine Ndiaye-Lobry,Anthony Deblasio,John Petrini,Martin Fleisher,Elena M Cortizas,Ramiro E Verdun,Megan A Hatlen,Chen Lossos

doi:10.1038/srep22760

Abstract

Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50s allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef−/−Rad50s/s mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50s and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation.

Highlights

Development of multiple myeloma, with whole genome sequencing of multiple myeloma samples identifying a mutation in the coding region of the Mre[11] gene[18,19], and gene expression profiling of multiple myeloma cells showing increased expression of NHEJ-related genes, such as Rad[50] and Xrcc[420]
The Mef−/− Rad50s/s mouse is a novel model of human multiple myeloma and plasma cell neoplasms; an abnormal proliferation of plasma cells is seen initially, accompanied by a monoclonal serum protein, mimicking monoclonal gammopathy of unknown significance (MGUS) or smoldering myeloma
While MGUS is generally recognized as a premalignant condition that progresses to multiple myeloma at a rate of about 1 percent per year[38], disease progression in this mouse model occurs with a much greater frequency

Summary

Introduction

Development of multiple myeloma, with whole genome sequencing of multiple myeloma samples identifying a mutation in the coding region of the Mre[11] gene[18,19], and gene expression profiling of multiple myeloma cells showing increased expression of NHEJ-related genes, such as Rad[50] and Xrcc[420]. We have analyzed the phenotypic and genomic abnormalities present in the Mef−/− Rad50s/s mice, establishing a novel and transplantable mouse model of multiple myeloma and plasma cell neoplasms which mimics the human disease and is not attributed to the activation of a specific oncogene or inactivation of a specific tumor suppressor gene (other than Mef). We have begun to clarify the mechanisms by which the Mef−/− Rad50s/s mice develop plasma cell neoplasms. We believe this mouse model will be useful for further analyzing disease initiation and progression, and for further pre-clinical screening of anti-myeloma compounds

Methods

Results

Conclusion