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
{"title":"Pathogenesis of diffuse large B cell lymphoma proteogenotypes.","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","doi":"10.1016/j.ccell.2026.05.008","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>+</sup> T cells. Our study identifies common oncogenic themes underlying high-risk DLBCL tumors and provides a proteogenomic framework for future diagnostic and therapeutic approaches.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1437-1457.e14"},"PeriodicalIF":56.1000,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2026.05.008","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/6/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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