Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Fabian Frontzek, Annette M. Staiger, Myroslav Zapukhlyak, Wendan Xu, Irina Bonzheim, Vanessa Borgmann, Philip Sander, Maria Joao Baptista, Jan-Niklas Heming, Philipp Berning, Ramona Wullenkord, Tabea Erdmann, Mathias Lutz, Pia Veratti, Sophia Ehrenfeld, Kirsty Wienand, Heike Horn, John R. Goodlad, Matthew R. Wilson, Ioannis Anagnostopoulos, Mario Lamping, Eva Gonzalez-Barca, Fina Climent, Antonio Salar, Josep Castellvi, Pau Abrisqueta, Javier Menarguez, Teresa Aldamiz, Julia Richter, Wolfram Klapper, Alexandar Tzankov, Stefan Dirnhofer, Andreas Rosenwald, José Luis Mate, Gustavo Tapia, Peter Lenz, Cornelius Miething, Wolfgang Hartmann, Björn Chapuy, Falko Fend, German Ott, José-Tomas Navarro, Michael Grau and Georg Lenz ()
Additional contact information
Fabian Frontzek: University Hospital Münster
Annette M. Staiger: Stuttgart and University of Tuebingen
Myroslav Zapukhlyak: University Hospital Münster
Wendan Xu: University Hospital Münster
Irina Bonzheim: University Hospital Tübingen
Vanessa Borgmann: University Hospital Tübingen
Philip Sander: University Hospital Tübingen
Maria Joao Baptista: Universitat Autònoma de Barcelona
Jan-Niklas Heming: University Hospital Münster
Philipp Berning: University Hospital Münster
Ramona Wullenkord: University Hospital Münster
Tabea Erdmann: University Hospital Münster
Mathias Lutz: University Hospital Münster
Pia Veratti: University Hospital Freiburg
Sophia Ehrenfeld: University of Freiburg
Kirsty Wienand: University Medical Center Göttingen
Heike Horn: Stuttgart and University of Tuebingen
John R. Goodlad: Queen Elizabeth University Hospital
Matthew R. Wilson: Beatson West of Scotland Cancer Centre
Ioannis Anagnostopoulos: University of Würzburg
Mario Lamping: Humboldt-Universität zu Berlin and Berlin Institute of Health
Eva Gonzalez-Barca: L’Hospitalet de Llobregat
Fina Climent: L’Hospitalet de Llobregat
Antonio Salar: Hospital del Mar
Josep Castellvi: Hospital Universitari Vall d’Hebron
Pau Abrisqueta: Hospital Universitari Vall d’Hebron
Javier Menarguez: Hospital Gregorio Marañón
Teresa Aldamiz: Hospital Gregorio Marañón
Julia Richter: Christian-Albrechts-University
Wolfram Klapper: Christian-Albrechts-University
Alexandar Tzankov: University Hospital Basel
Stefan Dirnhofer: University Hospital Basel
Andreas Rosenwald: University of Würzburg
José Luis Mate: Universitat Autònoma de Barcelona
Gustavo Tapia: Universitat Autònoma de Barcelona
Peter Lenz: University of Marburg
Cornelius Miething: University of Freiburg
Wolfgang Hartmann: University Hospital Münster
Björn Chapuy: University Medical Center Göttingen
Falko Fend: University Hospital Tübingen
German Ott: Robert Bosch Hospital
José-Tomas Navarro: Universitat Autònoma de Barcelona
Michael Grau: University Hospital Münster
Georg Lenz: University Hospital Münster

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25405-w

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DOI: 10.1038/s41467-021-25405-w

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