title: Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms.
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 Rad50(s) allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef(-/-)Rad50(s/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 Rad50(s) and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation.
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136 Miami, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Asai
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Hatlen
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136 Miami, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Lossos
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Ndiaye-Lobry
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Deblasio
authors.affiliation: Department of Laboratory Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York, USA.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murata
authors.affiliation: Department of Laboratory Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, FL 33136 Miami, USA.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Cortizas
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136 Miami, USA.|Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, FL 33136 Miami, USA.|Geriatric Research Education and Clinical Center, Miami Veterans Affairs Healthcare System, FL 33125 Miami, USA.
authors.forename: Ramiro E
authors.initials: RE
authors.lastname: Verdun
authors.affiliation: Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York, USA.
authors.forename: John
authors.initials: J
authors.lastname: Petrini
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136 Miami, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D017766:Acid Anhydride Hydrolases; D000818:Animals; D001773:Blood Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology / Q000637:transplantation; D015519:Bone Density; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D059472:Exome; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; C491779:Elf4 protein, mouse; D014157:Transcription Factors; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse