Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Frontzek, Fabian (University Hospital of Münster (Alemanya))
Staiger, Annette M. (Robert Bosch Hospital)
Zapukhlyak, Myroslav (University Hospital of Münster (Alemanya))
Xu, Wendan (University Hospital of Münster (Alemanya))
Bonzheim, Irina (University Hospital of Tübingen (Alemanya))
Borgmann, Vanessa (University Hospital of Tübingen (Alemanya))
Sander, Philip (University Hospital of Tübingen (Alemanya))
Baptista, Maria Joao (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Heming, Jan-Niklas (University Hospital of Münster (Alemanya))
Berning, Philipp (University Hospital of Münster (Alemanya))
Wullenkord, Ramona (University Hospital of Münster (Alemanya))
Erdmann, Tabea (University Hospital of Münster (Alemanya))
Lutz, Mathias (University Hospital of Münster (Alemanya))
Veratti, Pia (University Hospital Freiburg)
Ehrenfeld, Sophia (University of Freiburg)
Wienand, Kirsty (University Medical Center Göttingen)
Horn, Heike (Robert Bosch Hospital)
Goodlad, John R. (Queen Elizabeth University Hospital)
Wilson, Matthew R. (Beatson West of Scotland Cancer Centre (Glasgow, Regne Unit))
Anagnostopoulos, Ioannis (Charité - Universitätsmedizin Berlin)
Lamping, Mario (Charité - Universitätsmedizin Berlin)
González Barca, Eva (Universitat de Barcelona)
Climent, Fina (Institut d'Investigació Biomèdica de Bellvitge)
Salar, Antonio (Hospital del Mar (Barcelona, Catalunya))
Castellvi, Josep (Hospital Universitari Vall d'Hebron)
Abrisqueta, Pau (Hospital Universitari Vall d'Hebron)
Menarguez, Javier (Hospital General Universitario Gregorio Marañón)
Aldámiz-Echevarría, T (Hospital General Universitario Gregorio Marañón)
Richter, Julia (Christian-Albrechts-University)
Klapper, Wolfram (Christian-Albrechts-University)
Tzankov, Alexander (University Hospital Basel (Basilea, Suïssa))
Dirnhofer, Stefan (University Hospital Basel (Basilea, Suïssa))
Rosenwald, Andreas (University of Würzburg)
Mate Sanz, Jose Luís (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Tapia, Gustavo (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Lenz, Peter (Department of Physics. University of Marburg)
Miething, C. (German Cancer Research Center)
Hartmann, Wolfgang (University Hospital of Münster (Alemanya))
Chapuy, Björn (University Medical Center Göttingen)
Fend, Falko (University Hospital of Tübingen (Alemanya))
Ott, Gustav (Department of Clinical Pathology. Robert Bosch Hospital)
Navarro, José-Tomás (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Grau, Michael (University Hospital of Münster (Alemanya))
Lenz, Georg (University Hospital of Münster (Alemanya))
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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.
Nota:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	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
Publicat a:	Nature communications, Vol. 12 Núm. 1 (january 2021) , p. 5183, ISSN 2041-1723

DOI: 10.1038/s41467-021-25405-w
PMID: 34465776

14 p, 1.9 MB

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