Fluemann, Ruth, Rehkaemper, Tim, Nieper, Pascal, Pfeiffer, Pauline, Holzem, Alessandra, Klein, Sebastian ORCID: 0000-0002-2188-9377, Bhatia, Sanil ORCID: 0000-0001-6494-7744, Kochanek, Moritz, Kisis, Ilmars ORCID: 0000-0001-6207-3991, Pelzer, Benedikt W., Ahlert, Heinz, Hauer, Julia, Guerreiro, Alexandra da Palma, Ryan, Jeremy A., Reimann, Maurice, Riabinska, Arina, Wiederstein, Janica, Krueger, Marcus, Deckert, Martina, Altmueller, Janine, Klatt, Andreas R., Frenzel, Lukas P., Pasqualucci, Laura, Beguelin, Wendy, Melnick, Ari M., Sander, Sandrine, Montesinos-Rongen, Manuel ORCID: 0000-0003-4724-5526, Brunn, Anna, Lohneis, Philipp, Buettner, Reinhard, Kashkar, Hamid, Borkhardt, Arndt, Letai, Anthony, Persigehl, Thorsten, Peifer, Martin, Schmitt, Clemens A. ORCID: 0000-0002-4731-2226, Reinhardt, Hans Christian and Knittel, Gero ORCID: 0000-0001-8395-3701 (2021). An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities. Blood Cancer Discov., 2 (1). S. 70 - 92. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2643-3249

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Abstract

Based on gene expression profiles, diffuse large B-cell lymphoma (DLBCL) is subdivided 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 MYD88 as well as BCL2 copy-number gains. Here, we employ immune phenotyping, RNA sequencing, and wholeexome sequencing to characterize a Myd88- and BCL2-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 PD-L1 expression compared with GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and PD-1 blockade 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 MYD88 and BCL2 aberrations. SIGNIFICANCE: Oncogenic Myd88 and BCL2 cooperate in murine DLBCL lymphomagenesis. The resulting lymphomas display morphologic and transcriptomic features reminiscent of human ABC-DLBCL. Data derived from our Myd88/BCL2-driven autochthonous model demonstrate that combined BCL2 and PD-1 blockade displays substantial preclinical antilymphoma activity, providing preclinical proof-of-concept data, which pave the way for clinical translation.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fluemann, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehkaemper, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nieper, PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfeiffer, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzem, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDorcid.org/0000-0002-2188-9377UNSPECIFIED
Bhatia, SanilUNSPECIFIEDorcid.org/0000-0001-6494-7744UNSPECIFIED
Kochanek, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kisis, IlmarsUNSPECIFIEDorcid.org/0000-0001-6207-3991UNSPECIFIED
Pelzer, Benedikt W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahlert, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauer, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerreiro, Alexandra da PalmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryan, Jeremy A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reimann, MauriceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riabinska, ArinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiederstein, JanicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klatt, Andreas R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasqualucci, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beguelin, WendyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melnick, Ari M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, SandrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montesinos-Rongen, ManuelUNSPECIFIEDorcid.org/0000-0003-4724-5526UNSPECIFIED
Brunn, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohneis, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borkhardt, ArndtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Letai, AnthonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, Clemens A.UNSPECIFIEDorcid.org/0000-0002-4731-2226UNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knittel, GeroUNSPECIFIEDorcid.org/0000-0001-8395-3701UNSPECIFIED
URN: urn:nbn:de:hbz:38-603710
DOI: 10.1158/2643-3230.BCD-19-0059
Journal or Publication Title: Blood Cancer Discov.
Volume: 2
Number: 1
Page Range: S. 70 - 92
Date: 2021
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2643-3249
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NECROSIS-FACTOR-ALPHA; CLASS-SWITCH RECOMBINATION; CD8(+) T-CELLS; EXPRESSION; RITUXIMAB; ACTIVATION; SURVIVAL; PD-L1; TRANSPLANTATION; CLASSIFICATIONMultiple languages
Oncology; HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60371

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