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J Exp Med. 2015 Jun 1;212(6):833-43. doi: 10.1084/jem.20142009. Epub 2015 May 18.

Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.

Author information

1
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
2
Central European Institute of Technology, Masaryk University and University Hospital Brno, 601 77 Brno, Czech Republic.
3
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 CE Rotterdam, Netherlands.
4
The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
5
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, 141 86 Huddinge, Stockholm, Sweden.
6
Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
7
Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
8
Hematology Department, General Hospital of Nikea, 18454 Piraeus, Greece.
9
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, England, UK.
10
Department of Hematology, Pitié-Salpêtrière Hospital, F-75013 Paris, France Cordeliers Research Center, UMR_S 1138, UPMC University of Paris 6, F-75005 Paris, France.
11
Divisione di Oncologia Sperimentale, Dipartimento di Onco-Ematologia, IRCCS Istituto Scientifico San Raffaele and Fondazione Centro San Raffaele, 20132 Milano, Italy Università Vita-Salute San Raffaele, 20132 Milano, Italy.
12
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden Institute of Applied Biosciences, Center for Research and Technology Hellas, 57001 Thessaloniki, Greece.
13
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, 106 91 Stockholm, Sweden.
14
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden richard.rosenquist@igp.uu.se.

Abstract

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

PMID:
25987724
PMCID:
PMC4451125
DOI:
10.1084/jem.20142009
[Indexed for MEDLINE]
Free PMC Article

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