An autochthonous mouse model of Myd88- and BCL2-driven diffuse large B-cell lymphoma reveals actionable molecular vulnerabilities

Item Type:	Article
Title:	An autochthonous mouse model of Myd88- and BCL2-driven diffuse large B-cell lymphoma reveals actionable molecular vulnerabilities
Creators Name:	Flümann, R. and Rehkämper, T. and Nieper, P. and Pfeiffer, P. and Holzem, A. and Klein, S. and Bhatia, S. and Kochanek, M. and Kisis, I. and Pelzer, B.W. and Ahlert, H. and Hauer, J. and da Palma Guerreiro, A. and Ryan, J.A. and Reimann, M. and Riabinska, A. and Wiederstein, J. and Krüger, M. and Deckert, M. and Altmüller, J. and Klatt, A.R. and Frenzel, L.P. and Pasqualucci, L. and Béguelin, W. and Melnick, A.M. and Sander, S. and Montesinos-Rongen, M. and Brunn, A. and Lohneis, P. and Büttner, R. and Kashkar, H. and Borkhardt, A. and Letai, A. and Persigehl, T. and Peifer, M. and Schmitt, C.A. and Reinhardt, H.C. and Knittel, G.
Abstract:	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 MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq 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 to GCB-DLBCL. In vivo 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 MYD88 and BCL2 aberrations.
Keywords:	bcl-2 Genes, Diffuse Large B-Cell Lymphoma, Germinal Center, Myeloid Differentiation Factor 88, Proto-Oncogene Proteins c-bcl-2, Animals, Mice
Source:	Blood Cancer Discovery
ISSN:	2643-3230
Publisher:	American Association for Cancer Research
Volume:	2
Number:	1
Page Range:	70-91
Date:	January 2021
Additional Information:	Copyright ©2020 American Association for Cancer Research.
Official Publication:	https://doi.org/10.1158/2643-3230.BCD-19-0059
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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