RT Journal Article
SR Electronic
T1 An Autochthonous Mouse Model of <em>Myd88</em>- and <em>BCL2</em>-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities
JF Blood Cancer Discovery
JO Blood Cancer Discov
FD American Association for Cancer Research
SP 70
OP 91
DO 10.1158/2643-3230.BCD-19-0059
VO 2
IS 1
A1 Flümann, Ruth
A1 Rehkämper, Tim
A1 Nieper, Pascal
A1 Pfeiffer, Pauline
A1 Holzem, Alessandra
A1 Klein, Sebastian
A1 Bhatia, Sanil
A1 Kochanek, Moritz
A1 Kisis, Ilmars
A1 Pelzer, Benedikt W.
A1 Ahlert, Heinz
A1 Hauer, Julia
A1 da Palma Guerreiro, Alexandra
A1 Ryan, Jeremy A.
A1 Reimann, Maurice
A1 Riabinska, Arina
A1 Wiederstein, Janica
A1 Krüger, Marcus
A1 Deckert, Martina
A1 Altmüller, Janine
A1 Klatt, Andreas R.
A1 Frenzel, Lukas P.
A1 Pasqualucci, Laura
A1 Béguelin, Wendy
A1 Melnick, Ari M.
A1 Sander, Sandrine
A1 Montesinos-Rongen, Manuel
A1 Brunn, Anna
A1 Lohneis, Philipp
A1 Büttner, Reinhard
A1 Kashkar, Hamid
A1 Borkhardt, Arndt
A1 Letai, Anthony
A1 Persigehl, Thorsten
A1 Peifer, Martin
A1 Schmitt, Clemens A.
A1 Reinhardt, Hans Christian
A1 Knittel, Gero
YR 2021
UL http://bloodcancerdiscov.aacrjournals.org/content/2/1/70.abstract
AB 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.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.This article is highlighted in the In This Issue feature, p. 1