Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Frontzek, Fabian; Salar, 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

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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

Resumen

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.