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Mouse models of human multiple myeloma subgroups

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Item Type:Article
Title:Mouse models of human multiple myeloma subgroups
Creators Name:Winkler, W. and Farré Díaz, C. and Blanc, E. and Napieczynska, H. and Langner, P. and Werner, M. and Walter, B. and Wollert-Wulf, B. and Yasuda, T. and Heuser, A. and Beule, D. and Mathas, S. and Anagnostopoulos, I. and Rosenwald, A. and Rajewsky, K. and Janz, M.
Abstract:Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated genetically defined, subgroup-specific MM models by the GC B cell-specific coactivation of mouse Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NF-κB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency, and bone lesions. The transgenic plasma cells could be propagated in vivo and showed distinct transcriptional profiles, resembling their human MM counterparts. Thus, we show that targeting the expression of genes involved in MM subgroup-specific chromosomal translocations into mouse GC B cells translates into distinct MM-like diseases that recapitulate key features of the human tumors, opening the way to a better understanding of the pathogenesis and therapeutic vulnerabilities of different MM subgroups.
Keywords:Multiple Myeloma, Chromosomal Translocations, Translocation Subgroups, Cyclin D1/MMSET, Conditional Mouse Models, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:e2219439120
Date:7 March 2023
Official Publication:https://doi.org/10.1073/pnas.2219439120
PubMed:View item in PubMed

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