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


  • L. Mansouri
  • D. Noerenberg
  • E. Young
  • E. Mylonas
  • M. Abdulla
  • M. Frick
  • F. Asmar
  • V. Ljungstroem
  • M. Schneider
  • K. Yoshida
  • A. Skaftason
  • T. Pandzic
  • B. Gonzalez
  • A. Tasidou
  • N. Waldhueter
  • A. Rivas-Delgado
  • M. Angelopoulou
  • M. Ziepert
  • C.M. Arends
  • L. Couronne
  • D. Lenze
  • C.D. Baldus
  • C. Bastard
  • J. Okosun
  • J. Fitzgibbon
  • B. Doerken
  • H.G. Drexler
  • D. Roos-Weil
  • C.A. Schmitt
  • H.D. Munch-Petersen
  • T. Zenz
  • M.L. Hansmann
  • J.C. Strefford
  • G. Enblad
  • O.A. Bernard
  • E. Ralfkiaer
  • M. Erlanson
  • P. Korkolopoulou
  • M. Hultdin
  • T. Papadaki
  • K. Gronbaek
  • A. Lopez-Guillermo
  • S. Ogawa
  • R. Kueppers
  • K. Stamatopoulos
  • N. Stavroyianni
  • G. Kanellis
  • A. Rosenwald
  • E. Campo
  • R.M. Amini
  • G. Ott
  • T.P. Vassilakopoulos
  • M. Hummel
  • R. Rosenquist
  • F. Damm


  • Blood


  • Blood 128 (23): 2666-2670


  • We recently reported a truncating deletion in the NFKBIE gene, which encodes IkappaB, a negative feedback regulator of NF-kappaB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence 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 CNS lymphoma (3-4%). 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 to wildtype 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), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-kappaB 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.