title: Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Viktor
authors.initials: V
authors.lastname: Ljungström
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Sina
authors.initials: S
authors.lastname: Bondza
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Arngården
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Sujata
authors.initials: S
authors.lastname: Bhoi
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Larsson
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortese
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalushkova
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, 601 77 Brno, Czech Republic.
authors.forename: Karla
authors.initials: K
authors.lastname: Plevova
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Young
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Rebeqa
authors.initials: R
authors.lastname: Gunnarsson
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Falk-Sörqvist
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönn
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 CE Rotterdam, Netherlands.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Muggen
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, 141 86 Huddinge, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Enblad
authors.affiliation: Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Smedby
authors.affiliation: Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.affiliation: Hematology Department, General Hospital of Nikea, 18454 Piraeus, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rung
authors.affiliation: The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, England, UK.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 CE Rotterdam, Netherlands.
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, 601 77 Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: 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.
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Hellström
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.affiliation: 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.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: 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.
authors.forename: Mats
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden richard.rosenquist@igp.uu.se.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002869:Chromosome Aberrations; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D051550:I-kappa B Kinase