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

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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.


  • Larry Mansouri
  • Lesley-Ann Sutton
  • Viktor Ljungström
  • Sina Bondza
  • Linda Arngården
  • Sujata Bhoi
  • Jimmy Larsson
  • Diego Cortese
  • Antonia Kalushkova
  • Karla Plevova
  • Emma Young
  • Rebeqa Gunnarsson
  • Elin Falk-Sörqvist
  • Peter Lönn
  • Alice F Muggen
  • Xiao-Jie Yan
  • Birgitta Sander
  • Gunilla Enblad
  • Karin E Smedby
  • Chrysoula Belessi
  • Johan Rung
  • Nicholas Chiorazzi
  • Jonathan C Strefford
  • Anton W Langerak
  • Sarka Pospisilova
  • Frederic Davi
  • Mats Hellström
  • Helena Jernberg-Wiklund
  • Paolo Ghia
  • Ola Söderberg
  • Kostas Stamatopoulos
  • Mats Nilsson
  • Richard Rosenquist
External organisations
  • Uppsala University
  • Masaryk University
  • Erasmus University Medical Center
  • Feinstein Institute for Medical Research
  • Karolinska Institutet
  • Nikea General Hospital, Piraeus
  • University of Southampton
  • Pierre and Marie Curie University
  • University Vita-Salute San Raffaele
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Hematology
Original languageEnglish
Pages (from-to)833-843
JournalJournal of Experimental Medicine
Issue number6
Publication statusPublished - 2015
Publication categoryResearch

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