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Functional loss of ...
Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.
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- Mansouri, Larry (author)
- Uppsala universitet,Uppsala University,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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- Sutton, Lesley-Ann (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Ljungström, Viktor (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Bondza, Sina (author)
- Uppsala universitet,Uppsala University,Enheten för biomedicinsk strålningsvetenskap,Science for Life Laboratory, SciLifeLab
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- Arngården, Linda (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Molekylära verktyg
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- Bhoi, Sujata (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Larsson, Jimmy (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi
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- Cortese, Diego (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Kalushkova, Antonia (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Plevova, Karla (author)
- Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic
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- Young, Emma (author)
- Uppsala universitet,Uppsala University,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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- Gunnarsson, Rebeqa (author)
- Uppsala universitet,Uppsala University,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Falk Sörqvist, Elin (author)
- Uppsala universitet,Uppsala University,Molekylära verktyg,Science for Life Laboratory, SciLifeLab
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- Lönn, Peter (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Molekylära verktyg
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- Muggen, Alice F (author)
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
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- Yan, Xiao-Jie (author)
- The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America,
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- Sander, Birgitta (author)
- Karolinska Institutet,Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
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- Enblad, Gunilla (author)
- Uppsala universitet,Uppsala University,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Smedby, Karin E (author)
- Karolinska Institutet,Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden
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- Juliusson, Gunnar (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden
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- Belessi, Chrysoula (author)
- Hematology Department, General Hospital of Nikea, Piraeus, Greece
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- Rung, Johan (author)
- Uppsala universitet,Uppsala University,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Chiorazzi, Nicholas (author)
- The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
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- Strefford, Jonathan C (author)
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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- Langerak, Anton W (author)
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
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- Pospisilova, Sarka (author)
- Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic
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- Davi, Frederic (author)
- AP-HP, Hôpital Pitié-Salpêtrière, Department of Hematology, and Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
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- Hellström, Mats (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Jernberg Wiklund, Helena (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Ghia, Paolo (author)
- Division of Experimental Oncology, Department of Onco-Haematology, IRCCS Istituto Scientifico San Raffaele, Fondazione Centro San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy
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- Söderberg, Ola (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylära verktyg
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- Stamatopoulos, Kostas (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi,nstitute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
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- Nilsson, Mats (author)
- Uppsala universitet,Institutionen för genetik och patologi,Molekylära verktyg,Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
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- Rosenquist Brandell, Richard (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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(creator_code:org_t)
- 2015-05-18
- 2015
- English.
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 212:6, s. 833-843
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http://www.ncbi.nlm....
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https://lup.lub.lu.s...
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Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Mansouri, Larry
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Sutton, Lesley-A ...
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Ljungström, Vikt ...
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Bondza, Sina
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Arngården, Linda
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Bhoi, Sujata
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show more...
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Larsson, Jimmy
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Cortese, Diego
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Kalushkova, Anto ...
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Plevova, Karla
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Young, Emma
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Gunnarsson, Rebe ...
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Falk Sörqvist, E ...
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Lönn, Peter
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Muggen, Alice F
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Yan, Xiao-Jie
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Sander, Birgitta
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Enblad, Gunilla
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Smedby, Karin E
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Juliusson, Gunna ...
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Belessi, Chrysou ...
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Rung, Johan
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Chiorazzi, Nicho ...
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Strefford, Jonat ...
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Langerak, Anton ...
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Pospisilova, Sar ...
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Davi, Frederic
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Hellström, Mats
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Jernberg Wiklund ...
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Ghia, Paolo
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Söderberg, Ola
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Stamatopoulos, K ...
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Nilsson, Mats
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Rosenquist Brand ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Journal of Exper ...
- By the university
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Lund University
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Uppsala University
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Karolinska Institutet