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TitleAn Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.
Publication TypeJournal Article
Year of Publication2021
AuthorsFlümann, Ruth, Rehkämper Tim, Nieper Pascal, Pfeiffer Pauline, Holzem Alessandra, Klein Sebastian, Bhatia Sanil, Kochanek Moritz, Kisis Ilmars, Pelzer Benedikt W., Ahlert Heinz, Hauer Julia, Guerreiro Alexandra da Palma, Ryan Jeremy A., Reimann Maurice, Riabinska Arina, Wiederstein Janica, Krüger Marcus, Deckert Martina, Altmüller Janine, Klatt Andreas R., Frenzel Lukas P., Pasqualucci Laura, Béguelin Wendy, Melnick Ari M., Sander Sandrine, Montesinos-Rongen Manuel, Brunn Anna, Lohneis Philipp, Büttner Reinhard, Kashkar Hamid, Borkhardt Arndt, Letai Anthony, Persigehl Thorsten, Peifer Martin, Schmitt Clemens A., Reinhardt Hans Christian, and Knittel Gero
JournalBlood Cancer Discov
Volume2
Issue1
Pagination70-91
Date Published2021 01
ISSN2643-3249
KeywordsAnimals, Genes, bcl-2, Germinal Center, Lymphoma, Large B-Cell, Diffuse, Mice, Myeloid Differentiation Factor 88, Proto-Oncogene Proteins c-bcl-2
Abstract

<p>Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in , as well as copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a and -driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased expression, compared to GCB-DLBCL. experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring and aberrations.</p>

DOI10.1158/2643-3230.BCD-19-0059
Alternate JournalBlood Cancer Discov
PubMed ID33447829
PubMed Central IDPMC7806186
Grant ListR01 CA172492 / CA / NCI NIH HHS / United States