An Autochthonous Mouse Model ofMyd88- andBCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities
- 1 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Blood Cancer Discovery
- Vol. 2 (1), 70-91
- https://doi.org/10.1158/2643-3230.bcd-19-0059
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. 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. 1Keywords
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Funding Information
- German-Israeli Foundation for Research and Development (I-65-412.20-2016)
- Deutsche Forschungsgemeinschaft (KFO-286-RP2, RE 2246/13-1)
- Deutsche José Carreras Leukämie Stiftung (R12/08)
- Else Kröner-Fresenius Stiftung (EKFS-2014-A06)
- Else Kröner-Fresenius Stiftung (2016_Kolleg.19)
- Deutsche Krebshilfe (1117240, 70113041)
- German Ministry of Education and Research (01ZX1303A)
- Deutsche Krebshilfe (70112951)
- NIH NCI (2R01CA172492)
- Leukemia and Lymphoma Society (#6575-19)
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