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

Flümann, R.; Rehkämper, T.; Nieper, P.; Pfeiffer, P.; Holzem, A.; Klein, S.; Bhatia, S.; Kochanek, M.; Kisis, I.; Pelzer, B.W.; Ahlert, H.; Hauer, J.; da Palma Guerreiro, A.; Ryan, J.A.; Reimann, M.; Riabinska, A.; Wiederstein, J.; Krüger, M.; Deckert, M.; Altmüller, J.; Klatt, A.R.; Frenzel, L.P.; Pasqualucci, L.; Béguelin, W.; Melnick, A.M.; Sander, S.; Montesinos-Rongen, M.; Brunn, A.; Lohneis, P.; Büttner, R.; Kashkar, H.; Borkhardt, A.; Letai, A.; Persigehl, T.; Peifer, M.; Schmitt, C.A.; Reinhardt, H.C.; Knittel, G.

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

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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., Rehkämper, T., Nieper, P., Pfeiffer, P., Holzem, A., Klein, S., Bhatia, S., Kochanek, M., Kisis, I., Pelzer, B.W., Ahlert, H., Hauer, J., da Palma Guerreiro, A., Ryan, J.A., Reimann, M., Riabinska, A., Wiederstein, J., Krüger, M., Deckert, M., Altmüller, J., Klatt, A.R., Frenzel, L.P., Pasqualucci, L., Béguelin, W., Melnick, A.M., Sander, S., Montesinos-Rongen, M., Brunn, A., Lohneis, P., Büttner, R., Kashkar, H., Borkhardt, A., Letai, A., Persigehl, T., Peifer, M., Schmitt, C.A., 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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