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

Mansouri, Larry; Sutton, Lesley-Ann; Ljungström, Viktor; Bondza, Sina; Arngården, Linda; Bhoi, Sujata; Larsson, Jimmy; Cortese, Diego; Kalushkova, Antonia and Plevova, Karla, et al. (2015) In Journal of Experimental Medicine 212(6). p.833-843
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... (More)
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. (Less)
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Journal of Experimental Medicine
volume
212
issue
6
pages
833 - 843
publisher
Rockefeller University Press
external identifiers
  • pmid:25987724
  • wos:000355569300001
  • scopus:84959107133
ISSN
1540-9538
DOI
10.1084/jem.20142009
language
English
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yes
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894f4766-2b6e-4f20-862d-093cade5cc1a (old id 5448787)
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http://www.ncbi.nlm.nih.gov/pubmed/25987724?dopt=Abstract
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2015-06-05 00:12:41
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@article{894f4766-2b6e-4f20-862d-093cade5cc1a,
  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.},
  author       = {Mansouri, Larry and Sutton, Lesley-Ann and Ljungström, Viktor and Bondza, Sina and Arngården, Linda and Bhoi, Sujata and Larsson, Jimmy and Cortese, Diego and Kalushkova, Antonia and Plevova, Karla and Young, Emma and Gunnarsson, Rebeqa and Falk-Sörqvist, Elin and Lönn, Peter and Muggen, Alice F and Yan, Xiao-Jie and Sander, Birgitta and Enblad, Gunilla and Smedby, Karin E and Juliusson, Gunnar and Belessi, Chrysoula and Rung, Johan and Chiorazzi, Nicholas and Strefford, Jonathan C and Langerak, Anton W and Pospisilova, Sarka and Davi, Frederic and Hellström, Mats and Jernberg-Wiklund, Helena and Ghia, Paolo and Söderberg, Ola and Stamatopoulos, Kostas and Nilsson, Mats and Rosenquist, Richard},
  issn         = {1540-9538},
  language     = {eng},
  number       = {6},
  pages        = {833--843},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.},
  url          = {http://dx.doi.org/10.1084/jem.20142009},
  volume       = {212},
  year         = {2015},
}