%0 Journal Article
%A Flümann, Ruth
%A Hansen, Julia
%A Pelzer, Benedikt W
%A Nieper, Pascal
%A Lohmann, Tim
%A Kisis, Ilmars
%A Riet, Tobias
%A Kohlhas, Viktoria
%A Nguyen, Phuong-Hien
%A Peifer, Martin
%A Abedpour, Nima
%A Bosco, Graziella
%A Thomas, Roman K
%A Kochanek, Moritz
%A Knüfer, Jacqueline
%A Jonigkeit, Lorenz
%A Beleggia, Filippo
%A Holzem, Alessandra
%A Büttner, Reinhard
%A Lohneis, Philipp
%A Meinel, Jörn
%A Ortmann, Monika
%A Persigehl, Thorsten
%A Hallek, Michael
%A Calado, Dinis Pedro
%A Chmielewski, Markus
%A Klein, Lukas Sebastian
%A Göthert, Joachim R
%A Chapuy, Bjoern
%A Zevnik, Branko
%A Wunderlich, F Thomas
%A von Tresckow, Bastian
%A Jachimowicz, Ron D
%A Melnick, Ari M
%A Reinhardt, Hans Christian
%A Knittel, Gero
%T Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies.
%J Blood cancer discovery
%V 4
%N 1
%@ 2643-3230
%C Philadelphia, PA
%I American Association for Cancer Research
%M DKFZ-2023-00070
%P 78 - 97
%D 2023
%X Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell-specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, flow-cytometry, and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with prememory B cells and light-zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in five of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression, and were sensitive to antimurine-CD19-CAR-T cell therapy, in vivo.Relapsed/refractory DLBCL remains a major medical challenge, and most of these patients succumb to their disease. Here, we generated mouse models, faithfully recapitulating the biology of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confirmed activity of this regimen in pretreated non-GCB-DLBCL patients. See related commentary by Leveille et al., p. 8. This article is highlighted in the In This Issue feature, p. 1.
%K Humans
%K Mice
%K Animals
%K Myeloid Differentiation Factor 88: genetics
%K Myeloid Differentiation Factor 88: metabolism
%K B-Lymphocytes
%K Lymphoma, Large B-Cell, Diffuse: genetics
%K Lymphoma, Large B-Cell, Diffuse: therapy
%K Plasma Cells: metabolism
%K Plasma Cells: pathology
%K Proto-Oncogene Proteins c-bcl-2: genetics
%K Proto-Oncogene Proteins c-bcl-2: metabolism
%K Proto-Oncogene Proteins c-bcl-2: therapeutic use
%K Myeloid Differentiation Factor 88 (NLM Chemicals)
%K Proto-Oncogene Proteins c-bcl-2 (NLM Chemicals)
%K BCL2 protein, human (NLM Chemicals)
%K Myd88 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36346827
%2 pmc:PMC9816818
%R 10.1158/2643-3230.BCD-22-0007
%U https://inrepo02.dkfz.de/record/186701