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Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Authors :
Michael Grau
Kirsty Wienand
Pia Veratti
Gustavo Tapia
Tabea Erdmann
Eva González-Barca
Falko Fend
Jan-Niklas Heming
Björn Chapuy
Irina Bonzheim
Sophia Ehrenfeld
Alexandar Tzankov
Javier Menárguez
Mathias Lutz
Philip Sander
Matthew R. Wilson
José-Tomás Navarro
Julia Richter
Wolfram Klapper
Stefan Dirnhofer
Cornelius Miething
Pau Abrisqueta
Andreas Rosenwald
Fina Climent
Ioannis Anagnostopoulos
Mario Lamping
Wendan Xu
Annette M. Staiger
Georg Lenz
Myroslav Zapukhlyak
Philipp Berning
Vanessa Borgmann
Wolfgang Hartmann
Peter Lenz
Teresa Aldamiz
Fabian Frontzek
German Ott
Maria Joao Baptista
Josep Castellví
Antonio Salar
Jose Luis Mate
Heike Horn
John R. Goodlad
Ramona Wullenkord
Institut Català de la Salut
[Frontzek F, Zapukhlyak M, Xu W] Department of Medicine A, Department of Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany. [Staiger AM] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tübingen, Germany. Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany. [Bonzheim I, Borgmann V] Institute of Pathology and Neuropathology, Eberhard Karls University of TübingenComprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany. [Castellvi J] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Abrisqueta P] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
Source :
Dipòsit Digital de la UB, Universidad de Barcelona, Nature Communications, r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol, instname, Scientia, Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Publication Year :
2021
Publisher :
Springer Science and Business Media LLC, 2021.

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.<br />Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

Subjects

Subjects :
Male
Limfomes
Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::Whole Genome Sequencing::Whole Exome Sequencing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
medicine.medical_treatment
Gene Dosage
General Physics and Astronomy
Interferó
Aggressive lymphoma
Disease
Translocation, Genetic
Whole Exome Sequencing
Cohort Studies
hemic and lymphatic diseases
MCL1
Molecular Targeted Therapy
B-cell lymphoma
Càncer
Cancer genetics
Sistema limfàtic - Càncer - Mortalitat
Exome sequencing
Otros calificadores::/terapia [Otros calificadores]
Cancer
Aged, 80 and over
Multidisciplinary
Immunosuppression
Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell::Lymphoma, Large B-Cell, Diffuse::Plasmablastic Lymphoma [DISEASES]
Middle Aged
STAT Transcription Factors
Interferon Regulatory Factors
Plasmablastic Lymphoma
Female
técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN::secuenciación del genoma completo::secuenciación del exoma completo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS]
Adult
neoplasias::neoplasias por tipo histológico::linfoma::linfoma no Hodgkin::linfoma de células B::linfoma de células B grandes difuso::linfoma plasmablástico [ENFERMEDADES]
Adolescent
Science
Cèl·lules B
Mapatge cromosòmic humà
Cèl·lules B - Tumors - Tractament
General Biochemistry, Genetics and Molecular Biology
Article
Young Adult
Exome Sequencing
medicine
Mortalitat
Humans
Human gene mapping
Seqüència de nucleòtids
Aged
Janus Kinases
B cells
business.industry
Gene Expression Profiling
Gene Amplification
General Chemistry
Other subheadings::/therapy [Other subheadings]
medicine.disease
Cancer research
business
Plasmablastic lymphoma
Genètica
IRF4

Details

ISSN :
20411723
Database :
OpenAIRE
Journal :
Dipòsit Digital de la UB, Universidad de Barcelona, Nature Communications, r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol, instname, Scientia, Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Accession number :
edsair.doi.dedup.....0bd88233e6b47877ca5d45e25f3a08e7