Mansouri L, Noerenberg D, Young E, Mylonas E, Abdulla M, Frick M, Asmar F, Ljungström V, Schneider M, Yoshida K, Skaftason A, Pandzic T, Gonzalez B, Tasidou A, Waldhueter N, Rivas-Delgado A, Angelopoulou M, Ziepert M, Arends CM, Couronné L, Lenze D, Baldus CD, Bastard C, Okosun J, Fitzgibbon J, Dörken B, Drexler HG, Roos-Weil D, Schmitt CA, Munch-Petersen HD, Zenz T, Hansmann ML, Strefford JC, Enblad G, Bernard OA, Ralfkiaer E, Erlanson M, Korkolopoulou P, Hultdin M, Papadaki T, Grønbæk K, Lopez-Guillermo A, Ogawa S, Küppers R, Stamatopoulos K, Stavroyianni N, Kanellis G, Rosenwald A, Campo E, Amini RM, Ott G, Vassilakopoulos TP, Hummel M, Rosenquist R, Damm F
Blood 128 (23) 2666-2670 [2016-12-08; online 2016-09-28]
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.