Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

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 plasmacyt...

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Detalles Bibliográficos
Autores: Frontzek, Fabian|||0000-0003-1705-3638, Staiger, Annette M.|||0000-0002-5896-3200, Zapukhlyak, Myroslav, Xu, Wendan, Bonzheim, Irina, Borgmann, Vanessa, Sander, Philip, Baptista, Maria Joao|||0000-0003-3471-2535, Heming, Jan-Niklas, Berning, Philipp, Wullenkord, Ramona, Erdmann, Tabea, Lutz, Mathias|||0000-0002-2572-5687, Veratti, Pia, Ehrenfeld, Sophia, Wienand, Kirsty|||0000-0001-9548-4420, Horn, Heike, Goodlad, John R., Wilson, Matthew R.|||0000-0001-5423-3270, Anagnostopoulos, Ioannis, Lamping, Mario, González Barca, Eva|||0000-0002-1323-1508, Climent, Fina|||0000-0002-4360-8388, Salar Silvestre, Antonio|||0000-0002-4652-4825, Castellvi, Josep|||0000-0001-5745-9996, Abrisqueta, Pau|||0000-0001-9625-7422, Menarguez, Javier, Aldámiz-Echevarría, T., Richter, Julia|||0000-0002-9543-4084, Klapper, Wolfram|||0000-0001-7208-4117, Tzankov, Alexander|||0000-0002-1100-3819, Dirnhofer, Stefan, Rosenwald, Andreas|||0000-0001-7282-8374, Mate Sanz, Jose Luís|||0000-0002-4829-3426, Tapia, Gustavo|||0000-0003-1882-0368, Lenz, Peter, Miething, C., Hartmann, Wolfgang|||0000-0002-7609-5021, Chapuy, Björn, Fend, Falko|||0000-0002-5496-293X, Ott, Gustav, Navarro Ferrando, José Tomás|||0000-0001-9101-6013, Grau, Michael, Lenz, Georg|||0000-0002-4728-1693
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270642
Acceso en línea:https://ddd.uab.cat/record/270642
https://dx.doi.org/urn:doi:10.1038/s41467-021-25405-w
Access Level:acceso abierto
Palabra clave:Adolescent
Adult
Aged
Aged, 80 and over
Cohort Studies
Female
Gene Amplification
Gene Dosage
Gene Expression Profiling
Humans
Interferon Regulatory Factors
Janus Kinases
Male
Middle Aged
Molecular Targeted Therapy
Plasmablastic Lymphoma
STAT Transcription Factors
Translocation, Genetic
Whole Exome Sequencing
Young Adult
Descripción
Sumario: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.

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