Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
Authors
- 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
Journal
- Blood
Citation
- Blood 128 (23): 2666-2670
Abstract
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.