{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:18:05Z","timestamp":1791850685457,"version":"4.3.4"},"reference-count":34,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,6,1]]},"abstract":"<jats:p>NF-\u03baB 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-\u03baB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21\/315 cases; 7%), which encodes I\u03baB\u03b5, a negative regulator of NF-\u03baB 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 I\u03baB\u03b5 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 I\u03baB\u03b5 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-\u03baB deregulation during lymphomagenesis.<\/jats:p>","DOI":"10.1084\/jem.20142009","type":"journal-article","created":{"date-parts":[[2015,5,19]],"date-time":"2015-05-19T02:11:42Z","timestamp":1432001502000},"page":"833-843","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":97,"title":["Functional loss of I\u03baB\u03b5 leads to NF-\u03baB deregulation in aggressive chronic lymphocytic leukemia"],"prefix":"10.1084","volume":"212","author":[{"given":"Larry","family":"Mansouri","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 05 Uppsala, Sweden 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley-Ann","family":"Sutton","sequence":"additional","affiliation":[{"name":"Department of 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