Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Nat Commun. 2021 Aug 31;12(1):5183. doi: 10.1038/s41467-021-25405-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Interferon Regulatory Factors
  • STAT Transcription Factors
  • interferon regulatory factor-4
  • Janus Kinases