Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

We thank all patients and their physicians for trial participation. We thank Jan Mitschke who contributed to the bioinformatical analysis of the performed shRNA screen. This work was funded by a grant from German Cancer Aid to J.N.H. We thank the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad in Spain as well as the Josep Carreras International Foundation for funding to J.-T.N. 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.