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

• DOI: 10.1084/jem.20142009
• Publication Date: 2015-05-19T02:11:42Z
• Authors: 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. Stref...; Anton W. Langerak; Sarka Pospisilova; Frederic Davi; Mats Hellström; Helena Jernberg-W...; Paolo Ghia; Ola Söderberg; Kostas Stamatopoulos; Mats Nilsson; Richard Rosenquist
• Keywords: breakpoint cluster region; IκBα

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 pathway a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, negative regulator normal B cells. Strikingly, 13 these cases carried an identical 4-bp frameshift deletion, resulting truncated protein. Screening additional 377 revealed that aberrations predominated poor-prognostic patients were associated with inferior outcome. Minor subclones and/or clonal evolution also observed, thus potentially linking this recurrent event to disease progression. Compared wild-type patients, NFKBIE-deleted showed reduced IκBε protein levels decreased p65 inhibition, along increased phosphorylation nuclear translocation p65. Considering central role cell receptor (BcR) signaling pathobiology, it notable loss enriched aggressive distinctive stereotyped BcR, likely contributing their poor prognosis, leading altered response BcR inhibitors. Because deletions observed several other lymphomas, our findings suggest novel common mechanism deregulation during lymphomagenesis.