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

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

doi:10.1182/blood-2016-03-704528

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

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 CouronnéDido 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

Department of Clinical Medicine

47 Citations (Scopus)

Abstract

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκB, 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 5 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 5 .022) and displayed inferior outcome compared with wild-Type patients (5-year survival, 59% vs 78%; P 5 .034); however, they appeared to benefit from radiotherapy (P 5 .022) and rituximab-containing regimens (P 5 .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P 5 .003) and when restricting the analysis to immunochemotherapy-Treated patients (P 5 .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 language	English
Journal	Blood
Volume	128
Issue number	23
Pages (from-to)	2666-2670
Number of pages	5
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2016-03-704528
Publication status	Published - 8 Dec 2016

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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, C. M., ... Damm, F. (2016). Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood, 128(23), 2666-2670. https://doi.org/10.1182/blood-2016-03-704528

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, M-L, 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, R-M, Ott, G, Vassilakopoulos, TP, Hummel, M, Rosenquist, R & Damm, F 2016, 'Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma', Blood, vol. 128, no. 23, pp. 2666-2670. https://doi.org/10.1182/blood-2016-03-704528

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title = "Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma",

abstract = "We recently reported a truncating deletion in the NFKBIE gene, which encodes IκB, 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 5 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 5 .022) and displayed inferior outcome compared with wild-Type patients (5-year survival, 59% vs 78%; P 5 .034); however, they appeared to benefit from radiotherapy (P 5 .022) and rituximab-containing regimens (P 5 .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P 5 .003) and when restricting the analysis to immunochemotherapy-Treated patients (P 5 .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.",

author = "Larry Mansouri and Daniel Noerenberg and Emma Young and Elena Mylonas and Maysaa Abdulla and Mareike Frick and Fazila Asmar and Viktor Ljungstr{\"o}m and Markus Schneider and Kenichi Yoshida and Aron Skaftason and Tatjana Pandzic and Blanca Gonzalez and Anna Tasidou and Nils Waldhueter and Alfredo Rivas-Delgado and Maria Angelopoulou and Marita Ziepert and Arends, {Christopher Maximilian} and Lucile Couronn{\'e} and Dido Lenze and Baldus, {Claudia D} and Christian Bastard and Jessica Okosun and Jude Fitzgibbon and Bernd D{\"o}rken and Drexler, {Hans G} and Damien Roos-Weil and Schmitt, {Clemens A} and Munch-Petersen, {Helga D} and Thorsten Zenz and Martin-Leo Hansmann and Strefford, {Jonathan C} and Gunilla Enblad and Bernard, {Olivier A} and Elisabeth Ralfkiaer and Martin Erlanson and Penelope Korkolopoulou and Magnus Hultdin and Theodora Papadaki and Kirsten Gr{\o}nb{\ae}k and Armando Lopez-Guillermo and Seishi Ogawa and Ralf K{\"u}ppers and Kostas Stamatopoulos and Niki Stavroyianni and George Kanellis and Andreas Rosenwald and Elias Campo and Rose-Marie Amini and German Ott and Vassilakopoulos, {Theodoros P} and Michael Hummel and Richard Rosenquist and Frederik Damm",

note = "{\textcopyright} 2016 by The American Society of Hematology.",

year = "2016",

month = dec,

day = "8",

doi = "10.1182/blood-2016-03-704528",

language = "English",

volume = "128",

pages = "2666--2670",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

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TY - JOUR

T1 - Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma

AU - Mansouri, Larry

AU - Noerenberg, Daniel

AU - Young, Emma

AU - Mylonas, Elena

AU - Abdulla, Maysaa

AU - Frick, Mareike

AU - Asmar, Fazila

AU - Ljungström, Viktor

AU - Schneider, Markus

AU - Yoshida, Kenichi

AU - Skaftason, Aron

AU - Pandzic, Tatjana

AU - Gonzalez, Blanca

AU - Tasidou, Anna

AU - Waldhueter, Nils

AU - Rivas-Delgado, Alfredo

AU - Angelopoulou, Maria

AU - Ziepert, Marita

AU - Arends, Christopher Maximilian

AU - Couronné, Lucile

AU - Lenze, Dido

AU - Baldus, Claudia D

AU - Bastard, Christian

AU - Okosun, Jessica

AU - Fitzgibbon, Jude

AU - Dörken, Bernd

AU - Drexler, Hans G

AU - Roos-Weil, Damien

AU - Schmitt, Clemens A

AU - Munch-Petersen, Helga D

AU - Zenz, Thorsten

AU - Hansmann, Martin-Leo

AU - Strefford, Jonathan C

AU - Enblad, Gunilla

AU - Bernard, Olivier A

AU - Ralfkiaer, Elisabeth

AU - Erlanson, Martin

AU - Korkolopoulou, Penelope

AU - Hultdin, Magnus

AU - Papadaki, Theodora

AU - Grønbæk, Kirsten

AU - Lopez-Guillermo, Armando

AU - Ogawa, Seishi

AU - Küppers, Ralf

AU - Stamatopoulos, Kostas

AU - Stavroyianni, Niki

AU - Kanellis, George

AU - Rosenwald, Andreas

AU - Campo, Elias

AU - Amini, Rose-Marie

AU - Ott, German

AU - Vassilakopoulos, Theodoros P

AU - Hummel, Michael

AU - Rosenquist, Richard

AU - Damm, Frederik

PY - 2016/12/8

Y1 - 2016/12/8

N2 - We recently reported a truncating deletion in the NFKBIE gene, which encodes IκB, 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 5 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 5 .022) and displayed inferior outcome compared with wild-Type patients (5-year survival, 59% vs 78%; P 5 .034); however, they appeared to benefit from radiotherapy (P 5 .022) and rituximab-containing regimens (P 5 .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P 5 .003) and when restricting the analysis to immunochemotherapy-Treated patients (P 5 .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.

AB - We recently reported a truncating deletion in the NFKBIE gene, which encodes IκB, 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 5 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 5 .022) and displayed inferior outcome compared with wild-Type patients (5-year survival, 59% vs 78%; P 5 .034); however, they appeared to benefit from radiotherapy (P 5 .022) and rituximab-containing regimens (P 5 .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P 5 .003) and when restricting the analysis to immunochemotherapy-Treated patients (P 5 .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.

U2 - 10.1182/blood-2016-03-704528

DO - 10.1182/blood-2016-03-704528

M3 - Journal article

C2 - 27670424

SN - 0006-4971

VL - 128

SP - 2666

EP - 2670

JO - Blood

JF - Blood

IS - 23

ER -

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

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