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

Varování

Publikace nespadá pod Ekonomicko-správní fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

Autoři	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	ZVV_2015_057_1305252_Functional_loss_of_I_kappa_B.pdf
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.
Související projekty:	CEITEC - středoevropský technologický institut Molekulární charakterizace B buněčných receptorů a jejich vztah k evoluci genetických změn u chronické lymfocytární leukémie Next Generation Sequencing Platform for Targeted Personalized Therapy of Leukemia