TY  - JOUR
AU  - Flümann, Ruth
AU  - Hansen, Julia
AU  - Pelzer, Benedikt W
AU  - Nieper, Pascal
AU  - Lohmann, Tim
AU  - Kisis, Ilmars
AU  - Riet, Tobias
AU  - Kohlhas, Viktoria
AU  - Nguyen, Phuong-Hien
AU  - Peifer, Martin
AU  - Abedpour, Nima
AU  - Bosco, Graziella
AU  - Thomas, Roman K
AU  - Kochanek, Moritz
AU  - Knüfer, Jacqueline
AU  - Jonigkeit, Lorenz
AU  - Beleggia, Filippo
AU  - Holzem, Alessandra
AU  - Büttner, Reinhard
AU  - Lohneis, Philipp
AU  - Meinel, Jörn
AU  - Ortmann, Monika
AU  - Persigehl, Thorsten
AU  - Hallek, Michael
AU  - Calado, Dinis Pedro
AU  - Chmielewski, Markus
AU  - Klein, Lukas Sebastian
AU  - Göthert, Joachim R
AU  - Chapuy, Bjoern
AU  - Zevnik, Branko
AU  - Wunderlich, F Thomas
AU  - von Tresckow, Bastian
AU  - Jachimowicz, Ron D
AU  - Melnick, Ari M
AU  - Reinhardt, Hans Christian
AU  - Knittel, Gero
TI  - Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies.
JO  - Blood cancer discovery
VL  - 4
IS  - 1
SN  - 2643-3230
CY  - Philadelphia, PA
PB  - American Association for Cancer Research
M1  - DKFZ-2023-00070
SP  - 78 - 97
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Mice
KW  - Animals
KW  - Myeloid Differentiation Factor 88: genetics
KW  - Myeloid Differentiation Factor 88: metabolism
KW  - B-Lymphocytes
KW  - Lymphoma, Large B-Cell, Diffuse: genetics
KW  - Lymphoma, Large B-Cell, Diffuse: therapy
KW  - Plasma Cells: metabolism
KW  - Plasma Cells: pathology
KW  - Proto-Oncogene Proteins c-bcl-2: genetics
KW  - Proto-Oncogene Proteins c-bcl-2: metabolism
KW  - Proto-Oncogene Proteins c-bcl-2: therapeutic use
KW  - Myeloid Differentiation Factor 88 (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-bcl-2 (NLM Chemicals)
KW  - BCL2 protein, human (NLM Chemicals)
KW  - Myd88 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36346827
C2  - pmc:PMC9816818
DO  - DOI:10.1158/2643-3230.BCD-22-0007
UR  - https://inrepo02.dkfz.de/record/186701
ER  -