Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Fabian Frontzek, Annette M. Staiger, Myroslav Zapukhlyak, Wendan Xu, Irina Bonzheim, Vanessa Borgmann, Philip Sander, Maria João 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. Wilson, Ioannis Anagnostopoulos, Mario Lamping, Eva González‐Barca, Fina Climent, Antonio Salar, Josep Castellví, Pau Abrisqueta, Javier Menárguez, Teresa Aldámiz, Julia Richter, Wolfgang Hiddemann, Alexandar Tzankov, Stefan Dirnhofer, Andreas Rosenwald, José Luís Mate, Gustavo Tapia, Peter Lenz, Cornelius Miething, Wolfgang Hartmann, Bjoern Chapuy, Falko Fend, German Ott, José‐Tomás Navarro, Michael Grau, Georg Lenz
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.