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Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma

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  • Larry Mansouri
  • Daniel Noerenberg
  • Emma Young
  • Elena Mylonas
  • Maysaa Abdulla
  • Mareike Frick
  • Fazila Asmar
  • Viktor Ljungström
  • Markus Schneider
  • Kenichi Yoshida
  • Aron Skaftason
  • Tatjana Pandzic
  • Blanca Gonzalez
  • Anna Tasidou
  • Nils Waldhueter
  • Alfredo Rivas-Delgado
  • Maria Angelopoulou
  • Marita Ziepert
  • Christopher Maximilian Arends
  • Lucile Couronné
  • Dido Lenze
  • Claudia D Baldus
  • Christian Bastard
  • Jessica Okosun
  • Jude Fitzgibbon
  • Bernd Dörken
  • Hans G Drexler
  • Damien Roos-Weil
  • Clemens A Schmitt
  • Helga D Munch-Petersen
  • Thorsten Zenz
  • Martin-Leo Hansmann
  • Jonathan C Strefford
  • Gunilla Enblad
  • Olivier A Bernard
  • Elisabeth Ralfkiaer
  • Martin Erlanson
  • Penelope Korkolopoulou
  • Magnus Hultdin
  • Theodora Papadaki
  • Kirsten Grønbæk
  • Armando Lopez-Guillermo
  • Seishi Ogawa
  • Ralf Küppers
  • Kostas Stamatopoulos
  • Niki Stavroyianni
  • George Kanellis
  • Andreas Rosenwald
  • Elias Campo
  • Rose-Marie Amini
  • German Ott
  • Theodoros P Vassilakopoulos
  • Michael Hummel
  • Richard Rosenquist
  • Frederik Damm
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We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

Original languageEnglish
JournalBlood
Volume128
Issue number23
Pages (from-to)2666-2670
Number of pages5
ISSN0006-4971
DOIs
Publication statusPublished - 8 Dec 2016

ID: 49464986