MANSOURI, Larry, Lesley-Ann SUTTON, Viktor LJUNGSTROM, Sina BONDZA, Linda ARNGARDEN, Sujata BHOI, Jimmy LARSSON, Diego CORTESE, Antonia KALUSHKOVA, Karla PLEVOVÁ, Erin YOUNG, Rebeqa GUNNARSSON, Elin FALK-SORQVIST, Peter LONN, Alice F. MUGGEN, Xiao-Jie YAN, Brigitta SANDER, Gunilla ENBLAD, Karin E. SMEDBY, Gunnar JULIUSSON, Chrysoula BELESSI, Johan RUNG, Nicholas CHIORAZZI, Jonathan C. STREFFORD, Anton W. LANGERAK, Šárka POSPÍŠILOVÁ, Frederic DAVI, Mats HELLSTROM, Helena JERNBERG-WIKLUND, Paolo GHIA, Ola SODERBERG, Kostas STAMATOPOULOS, Marcus Lars Vittorio NILSSON and Richard ROSENQUIST. Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia. The Journal of Experimental Medicine. New York: Rockefeller University Press, 2015, vol. 212, No 6, p. 833-843. ISSN 0022-1007. doi:10.1084/jem.20142009.
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Basic information
Original name Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia
Authors MANSOURI, Larry (752 Sweden), Lesley-Ann SUTTON (752 Sweden), Viktor LJUNGSTROM (752 Sweden), Sina BONDZA (752 Sweden), Linda ARNGARDEN (752 Sweden), Sujata BHOI (752 Sweden), Jimmy LARSSON (752 Sweden), Diego CORTESE (752 Sweden), Antonia KALUSHKOVA (752 Sweden), Karla PLEVOVÁ (203 Czech Republic, belonging to the institution), Erin YOUNG (840 United States of America), Rebeqa GUNNARSSON (752 Sweden), Elin FALK-SORQVIST (752 Sweden), Peter LONN (752 Sweden), Alice F. MUGGEN (528 Netherlands), Xiao-Jie YAN (840 United States of America), Brigitta SANDER (752 Sweden), Gunilla ENBLAD (752 Sweden), Karin E. SMEDBY (752 Sweden), Gunnar JULIUSSON (752 Sweden), Chrysoula BELESSI (300 Greece), Johan RUNG (752 Sweden), Nicholas CHIORAZZI (840 United States of America), Jonathan C. STREFFORD (826 United Kingdom of Great Britain and Northern Ireland), Anton W. LANGERAK (528 Netherlands), Šárka POSPÍŠILOVÁ (203 Czech Republic, guarantor, belonging to the institution), Frederic DAVI (250 France), Mats HELLSTROM (752 Sweden), Helena JERNBERG-WIKLUND (752 Sweden), Paolo GHIA (380 Italy), Ola SODERBERG (752 Sweden), Kostas STAMATOPOULOS (300 Greece), Marcus Lars Vittorio NILSSON (752 Sweden) and Richard ROSENQUIST (752 Sweden).
Edition The Journal of Experimental Medicine, New York, Rockefeller University Press, 2015, 0022-1007.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30102 Immunology
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 11.240
RIV identification code RIV/00216224:14740/15:00083304
Organization unit Central European Institute of Technology
Doi http://dx.doi.org/10.1084/jem.20142009
UT WoS 000355569300001
Keywords in English CELL LYMPHOMA; MUTATIONS; ACTIVATION; RECEPTORS; PHENOTYPE; PATTERNS; SUBSETS; CANCER
Tags podil, rivok
Tags International impact, Reviewed
Changed by Changed by: Mgr. Eva Špillingová, učo 110713. Changed: 30. 3. 2016 13:31.
Abstract
NF-kappa B 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-kappa B 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 kappa B epsilon, a negative regulator of NF-kappa B 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 kappa B epsilon 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 kappa B epsilon 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-kappa B deregulation during lymphomagenesis.
Links
ED1.1.00/02.0068, research and development projectName: CEITEC - central european institute of technology
NT13493, research and development projectName: Molekulární charakterizace B buněčných receptorů a jejich vztah k evoluci genetických změn u chronické lymfocytární leukémie
7E13008, research and development projectName: Next Generation Sequencing Platform for Targeted Personalized Therapy of Leukemia (Acronym: NGS-PTL)
Investor: Ministry of Education, Youth and Sports of the CR
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