Pathogenesis of diffuse large B cell lymphoma proteogenotypes
Year: 2026
Type: article
Study design: Observational Study
Abstract: The clinical and molecular heterogeneity of diffuse large B cell lymphoma (DLBCL) is incompletely understood. By integrating proteomic, transcriptomic, and genomic data from 478 DLBCL tumors, we identify seven DLBCL proteogenotypes (PGs) reflecting specific pathophysiological features that span known molecular subtypes. PG4 is associated with poor outcome independent of established risk factors such as cell-of-origin, international prognostic index, or genetic features. PG4 contains activated B cell-like and germinal center B cell-like tumors and genetically unclassified cases. It shares a dark-zone-related B cell phenotype and shows enrichment for BTG1 mutations that can activate MYC. Single-cell sequencing and spatial transcriptomics reveal enhanced MYC and TCF3/4 transcriptional activity irrespective of MYC translocations. The PG4 tumor microenvironment is characterized by exhausted CD8 + T cells. Our study identifies common oncogenic themes underlying high-risk DLBCL tumors and provides a proteogenomic framework for future diagnostic and therapeutic approaches.
Source: Cancer Cell
Authors: Julius C. Enssle, Björn Häupl, Arber Qoku, Boya Wang, George W. Wright, Sharon Barrans, Yulai Zhou, Matthew A. Care, Cathy Burton, Caitlin Gribbin, Jennifer Ziello, Jason Weirather, Yibo Dai, Atish Kizhakeyil, Xubin Li, James D. Phelan, Smriti Kanangat, Stephan Eckert, Sebastian Scheich, Sebastian Wolf, Da Wei Huang, Josefine Jakob, Sebastian P. Perner, Andrea Di Fonzo, Martine Pape, Marion Bodach, Dominique Jahn, Uwe Plessmann, Annette M. Staiger, German Ott, Philipp Berning, Georg Lenz, Daniel J. Hodson, Bernhard Kuster, Roland Schmitz, Henning Urlaub, Michael R. Green, Ari M. Melnick, Reuben Tooze, Coraline Mlynarczyk, Giorgio Inghirami, Florian Buettner, Louis M. Staudt, Thomas Oellerich
Institutions: Goethe University Frankfurt, National Institutes of Health, University Hospital Frankfurt, National Cancer Institute, Frankfurt Cancer Institute, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, St James's University Hospital, Yale Cancer Center, Yale University, University of Leeds, Weill Cornell Medicine, Cell Signaling Technology (United States), The University of Texas MD Anderson Cancer Center, Emory University, Technical University of Munich, Max Planck Institute for Multidisciplinary Sciences, Robert Bosch Hospital, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, University Hospital Münster, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Justus-Liebig-Universität Gießen, Universitätsmedizin Göttingen, NewYork–Presbyterian Hospital, Josep Carreras Leukaemia Research Institute
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: U.S. Department of Health and Human Services, Leukemia and Lymphoma Society, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, European Commission, Deutsche Forschungsgemeinschaft, Fraunhofer-Gesellschaft, Hessisches Ministerium für Wissenschaft und Kunst, Deutsche Krebshilfe, National Institutes of Health, European Research Council, NIHR Imperial Biomedical Research Centre, Leeds Biomedical Research Centre, NIHR Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Institute, University of Cambridge
Awards: G139696651, G1912862370, G1949475607, G1968525704, G299057155, G4336557980, G4895081800, G5393252362, G5491712332, Proteogenomische Charakterisierung des diffus großzelligen BZellLymphoms, G5788000058, G5863156629, SFB 1530: Aufklärung und Targeting pathogener Mechanismen bei BZellNeoplasien, Cambridge Stem Cell Institute, G7568626180
OpenAlex ID: W7163520211