Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Josep Castellvi, 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. WilsonIoannis Anagnostopoulos, Mario Lamping, Eva González Barca, Fina Climent, Antonio Salar, Pau Abrisqueta, Javier Menarguez, T Aldámiz-Echevarría, Julia Richter, Wolfram Klapper, Alexander Tzankov, Stefan Dirnhofer, Andreas Rosenwald, Jose Luís Mate Sanz, Gustavo Tapia, Peter Lenz, C. Miething, Wolfgang Hartmann, Björn Chapuy, Falko Fend, Gustav Ott, José-Tomás Navarro, Michael Grau, Georg Lenz

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

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.
Original languageEnglish
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 2021

Keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Female
  • Gene Amplification
  • Gene Dosage
  • Gene Expression Profiling
  • Humans
  • Interferon Regulatory Factors
  • Janus Kinases
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Plasmablastic Lymphoma
  • STAT Transcription Factors
  • Translocation, Genetic
  • Whole Exome Sequencing
  • Young Adult

Fingerprint

Dive into the research topics of 'Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma'. Together they form a unique fingerprint.

Cite this