Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Frontzek, Fabian; Salar Silvestre, Antonio; Lenz, Georg

doi:http://dx.doi.org/10.1038/s41467-021-25405-w

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

License

Citation

Frontzek F, Staiger AM, Zapukhlyak M, Xu W, Bonzheim I, Borgmann V, et al. 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

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.