Journal Article (Editorial)

DKFZ-2023-00070

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies.

Flümann, R. ; Hansen, J. ; Pelzer, B. W. ; Nieper, P. ; Lohmann, T. ; Kisis, I. ; Riet, T. ; Kohlhas, V. ; Nguyen, P.-H. ; Peifer, M. ; Abedpour, N. ; Bosco, G. ; Thomas, R. K. ; Kochanek, M. ; Knüfer, J. ; Jonigkeit, L. ; Beleggia, F. ; Holzem, A. ; Büttner, R. ; Lohneis, P. ; Meinel, J. ; Ortmann, M. ; Persigehl, T. ; Hallek, M. ; Calado, D. P. ; Chmielewski, M. ; Klein, L. S.DKFZ* ; Göthert, J. R.DKFZ* ; Chapuy, B. ; Zevnik, B. ; Wunderlich, F. T. ; von Tresckow, B.DKFZ* ; Jachimowicz, R. D. ; Melnick, A. M. ; Reinhardt, H. C.DKFZ* ; Knittel, G.DKFZ*

2023
American Association for Cancer Research Philadelphia, PA

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Please use a persistent id in citations: doi:10.1158/2643-3230.BCD-22-0007

Abstract: 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.

Keyword(s): Humans (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Myeloid Differentiation Factor 88: genetics (MeSH) ; Myeloid Differentiation Factor 88: metabolism (MeSH) ; B-Lymphocytes (MeSH) ; Lymphoma, Large B-Cell, Diffuse: genetics (MeSH) ; Lymphoma, Large B-Cell, Diffuse: therapy (MeSH) ; Plasma Cells: metabolism (MeSH) ; Plasma Cells: pathology (MeSH) ; Proto-Oncogene Proteins c-bcl-2: genetics (MeSH) ; Proto-Oncogene Proteins c-bcl-2: metabolism (MeSH) ; Proto-Oncogene Proteins c-bcl-2: therapeutic use (MeSH) ; Myeloid Differentiation Factor 88 ; Proto-Oncogene Proteins c-bcl-2 ; BCL2 protein, human ; Myd88 protein, mouse

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Contributing Institute(s):

1. DKTK ED ES zentral (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; Clarivate Analytics Master Journal List ; Emerging Sources Citation Index ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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