dataset
posted on 2023-04-04, 00:44 authored by Ruth Flümann, Tim Rehkämper, Pascal Nieper, Pauline Pfeiffer, Alessandra Holzem, Sebastian Klein, Sanil Bhatia, Moritz Kochanek, Ilmars Kisis, Benedikt W. Pelzer, Heinz Ahlert, Julia Hauer, Alexandra da Palma Guerreiro, Jeremy A. Ryan, Maurice Reimann, Arina Riabinska, Janica Wiederstein, Marcus Krüger, Martina Deckert, Janine Altmüller, Andreas R. Klatt, Lukas P. Frenzel, Laura Pasqualucci, Wendy Béguelin, Ari M. Melnick, Sandrine Sander, Manuel Montesinos-Rongen, Anna Brunn, Philipp Lohneis, Reinhard Büttner, Hamid Kashkar, Arndt Borkhardt, Anthony Letai, Thorsten Persigehl, Martin Peifer, Clemens A. Schmitt, Hans Christian Reinhardt, Gero Knittel Pharmacological Screen IC50 values
Funding
German-Israeli Foundation for Research and Development
Deutsche Forschungsgemeinschaft
Deutsche Jose Carreras Leukämie Stiftung
Else Kröner-Fresenius Stiftung
Deutsche Krebshilfe
German Ministry of Education and Research
NIH
NCI
Leukemia and Lymphoma Society
History
ARTICLE 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 whole-exome 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.
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.This article is highlighted in the In This Issue feature, p. 1
