Informace o publikaci

Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia

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MANSOURI Larry SUTTON Lesley-Ann LJUNGSTROM Viktor BONDZA Sina ARNGARDEN Linda BHOI Sujata LARSSON Jimmy CORTESE Diego KALUSHKOVA Antonia PLEVOVÁ Karla YOUNG Erin GUNNARSSON Rebeqa FALK-SORQVIST Elin LONN Peter MUGGEN Alice F. YAN Xiao-Jie SANDER Brigitta ENBLAD Gunilla SMEDBY Karin E. JULIUSSON Gunnar BELESSI Chrysoula RUNG Johan CHIORAZZI Nicholas STREFFORD Jonathan C. LANGERAK Anton W. POSPÍŠILOVÁ Šárka DAVI Frederic HELLSTROM Mats JERNBERG-WIKLUND Helena GHIA Paolo SODERBERG Ola STAMATOPOULOS Kostas NILSSON Marcus Lars Vittorio ROSENQUIST Richard

Rok publikování 2015
Druh Článek v odborném periodiku
Časopis / Zdroj The Journal of Experimental Medicine
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www http://jem.rupress.org/content/212/6/830.full.pdf+html
Doi http://dx.doi.org/10.1084/jem.20142009
Obor Imunologie
Klíčová slova CELL LYMPHOMA; MUTATIONS; ACTIVATION; RECEPTORS; PHENOTYPE; PATTERNS; SUBSETS; CANCER
Přiložené soubory
Popis 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.
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