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

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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-/-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.

Original languageEnglish (US)
Article number22760
JournalScientific Reports
Volume6
DOIs
StatePublished - Mar 10 2016

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Plasma Cell Neoplasms
Plasma Cells
Multiple Myeloma
Exome
Oncogenes
Bone Density
Anemia
Neoplasms
Transcription Factors
Animal Models
Alleles
Cell Proliferation
Mutation
Proteins

ASJC Scopus subject areas

  • General

Cite this

Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms. / Asai, Takashi; Hatlen, Megan A.; Lossos, Chen; Ndiaye-Lobry, Delphine; Deblasio, Anthony; Murata, Kazunori; Fleisher, Martin; Cortizas, Elena M.; Verdun, Ramiro E; Petrini, John; Nimer, Stephen D.

In: Scientific Reports, Vol. 6, 22760, 10.03.2016.

Research output: Contribution to journalArticle

Asai, T, Hatlen, MA, Lossos, C, Ndiaye-Lobry, D, Deblasio, A, Murata, K, Fleisher, M, Cortizas, EM, Verdun, RE, Petrini, J & Nimer, SD 2016, 'Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms', Scientific Reports, vol. 6, 22760. https://doi.org/10.1038/srep22760
Asai, Takashi ; Hatlen, Megan A. ; Lossos, Chen ; Ndiaye-Lobry, Delphine ; Deblasio, Anthony ; Murata, Kazunori ; Fleisher, Martin ; Cortizas, Elena M. ; Verdun, Ramiro E ; Petrini, John ; Nimer, Stephen D. / Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms. In: Scientific Reports. 2016 ; Vol. 6.
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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-/-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.",
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