Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
06 01 2023
06 01 2023
Historique:
received:
20
01
2022
revised:
06
10
2022
accepted:
04
11
2022
pubmed:
9
11
2022
medline:
10
1
2023
entrez:
8
11
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36346827
pii: 712650
doi: 10.1158/2643-3230.BCD-22-0007
pmc: PMC9816818
doi:
Substances chimiques
Myeloid Differentiation Factor 88
0
Proto-Oncogene Proteins c-bcl-2
0
BCL2 protein, human
0
Myd88 protein, mouse
0
Types de publication
Editorial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
78-97Subventions
Organisme : German-Israeli Foundation for Scientific Research and Development (GIF)
ID : I-65-412.20-2016
Organisme : Deutsche Krebshilfe (German Cancer Aid)
ID : 1117240 and 70113041
Organisme : Deutsche Jose Carreras Leukämie-Stiftung
ID : R12/08
Organisme : Bundesministerium für Bildung und Forschung (BMBF)
ID : e:Med 01ZX1303A
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : RE 2246/13-1
Organisme : Else Kröner-Fresenius-Stiftung (EKFS)
ID : EKFS-2014-A06
Organisme : Medical Research Council
ID : MR/J008060/1
Pays : United Kingdom
Organisme : Else Kröner-Fresenius-Stiftung (EKFS)
ID : 2016_Kolleg.19
Organisme : Dr. Mildred Scheel Stiftung für Krebsforschung
ID : 70113307
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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