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

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Author

  • 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
  • Gunnar Juliusson
  • 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
Show all

Summary, in English

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.

Department/s

  • Stem Cell Center
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2015

Language

English

Pages

833-843

Publication/Series

Journal of Experimental Medicine

Volume

212

Issue

6

Document type

Journal article

Publisher

Rockefeller University Press

Topic

  • Cell and Molecular Biology
  • Hematology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1540-9538