TY - JOUR
T1 - Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.
AU - Mansouri, Larry
AU - Sutton, Lesley-Ann
AU - Ljungström, Viktor
AU - Bondza, Sina
AU - Arngården, Linda
AU - Bhoi, Sujata
AU - Larsson, Jimmy
AU - Cortese, Diego
AU - Kalushkova, Antonia
AU - Plevova, Karla
AU - Young, Emma
AU - Gunnarsson, Rebeqa
AU - Falk-Sörqvist, Elin
AU - Lönn, Peter
AU - Muggen, Alice F
AU - Yan, Xiao-Jie
AU - Sander, Birgitta
AU - Enblad, Gunilla
AU - Smedby, Karin E
AU - Juliusson, Gunnar
AU - Belessi, Chrysoula
AU - Rung, Johan
AU - Chiorazzi, Nicholas
AU - Strefford, Jonathan C
AU - Langerak, Anton W
AU - Pospisilova, Sarka
AU - Davi, Frederic
AU - Hellström, Mats
AU - Jernberg-Wiklund, Helena
AU - Ghia, Paolo
AU - Söderberg, Ola
AU - Stamatopoulos, Kostas
AU - Nilsson, Mats
AU - Rosenquist, Richard
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1084/jem.20142009
DO - 10.1084/jem.20142009
M3 - Article
C2 - 25987724
SN - 1540-9538
VL - 212
SP - 833
EP - 843
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
ER -