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Mouse models of human multiple myeloma subgroups

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...

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Autores principales: Winkler, Wiebke, Farré Díaz, Carlota, Blanc, Eric, Napieczynska, Hanna, Langner, Patrick, Werner, Marvin, Walter, Barbara, Wollert-Wulf , Brigitte, Yasuda, Tomoharu, Heuser, Arnd, Beule, Dieter, Mathas, Stephan, Anagnostopoulos, Ioannis, Rosenwald, Andreas, Rajewsky, Klaus, Janz, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013859/
https://www.ncbi.nlm.nih.gov/pubmed/36853944
http://dx.doi.org/10.1073/pnas.2219439120
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author Winkler, Wiebke
Farré Díaz, Carlota
Blanc, Eric
Napieczynska, Hanna
Langner, Patrick
Werner, Marvin
Walter, Barbara
Wollert-Wulf , Brigitte
Yasuda, Tomoharu
Heuser, Arnd
Beule, Dieter
Mathas, Stephan
Anagnostopoulos, Ioannis
Rosenwald, Andreas
Rajewsky, Klaus
Janz, Martin
author_facet Winkler, Wiebke
Farré Díaz, Carlota
Blanc, Eric
Napieczynska, Hanna
Langner, Patrick
Werner, Marvin
Walter, Barbara
Wollert-Wulf , Brigitte
Yasuda, Tomoharu
Heuser, Arnd
Beule, Dieter
Mathas, Stephan
Anagnostopoulos, Ioannis
Rosenwald, Andreas
Rajewsky, Klaus
Janz, Martin
author_sort Winkler, Wiebke
collection PubMed
description 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.
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spelling pubmed-100138592023-08-28 Mouse models of human multiple myeloma subgroups Winkler, Wiebke Farré Díaz, Carlota Blanc, Eric Napieczynska, Hanna Langner, Patrick Werner, Marvin Walter, Barbara Wollert-Wulf , Brigitte Yasuda, Tomoharu Heuser, Arnd Beule, Dieter Mathas, Stephan Anagnostopoulos, Ioannis Rosenwald, Andreas Rajewsky, Klaus Janz, Martin Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-02-28 2023-03-07 /pmc/articles/PMC10013859/ /pubmed/36853944 http://dx.doi.org/10.1073/pnas.2219439120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Winkler, Wiebke
Farré Díaz, Carlota
Blanc, Eric
Napieczynska, Hanna
Langner, Patrick
Werner, Marvin
Walter, Barbara
Wollert-Wulf , Brigitte
Yasuda, Tomoharu
Heuser, Arnd
Beule, Dieter
Mathas, Stephan
Anagnostopoulos, Ioannis
Rosenwald, Andreas
Rajewsky, Klaus
Janz, Martin
Mouse models of human multiple myeloma subgroups
title Mouse models of human multiple myeloma subgroups
title_full Mouse models of human multiple myeloma subgroups
title_fullStr Mouse models of human multiple myeloma subgroups
title_full_unstemmed Mouse models of human multiple myeloma subgroups
title_short Mouse models of human multiple myeloma subgroups
title_sort mouse models of human multiple myeloma subgroups
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013859/
https://www.ncbi.nlm.nih.gov/pubmed/36853944
http://dx.doi.org/10.1073/pnas.2219439120
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