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

J 2015

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

MANSOURI, Larry; Lesley-Ann SUTTON; Viktor LJUNGSTROM; Sina BONDZA; Linda ARNGARDEN et al.

Základní údaje

Originální název

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

Autoři

Vydání

The Journal of Experimental Medicine, New York, Rockefeller University Press, 2015, 0022-1007

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30102 Immunology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 11.240

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/15:00083304

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

CELL LYMPHOMA; MUTATIONS; ACTIVATION; RECEPTORS; PHENOTYPE; PATTERNS; SUBSETS; CANCER

Štítky

podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 30. 3. 2016 13:31, Mgr. Eva Špillingová

Anotace

V originále

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.

Návaznosti

ED1.1.00/02.0068, projekt VaV

Název: CEITEC - central european institute of technology

NT13493, projekt VaV

Název: Molekulární charakterizace B buněčných receptorů a jejich vztah k evoluci genetických změn u chronické lymfocytární leukémie

7E13008, projekt VaV

Název: Next Generation Sequencing Platform for Targeted Personalized Therapy of Leukemia (Akronym: NGS-PTL)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Next Generation Sequencing Platform for Targeted Personalized Therapy of Leukemia

Přiložené soubory

ZVV_2015_057_1305252_Functional_loss_of_I_kappa_B.pdf

Požádat o autorskou verzi souboru

Citovat

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 a 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, roč. 212, č. 6, s. 833-843. ISSN 0022-1007. Dostupné z: https://doi.org/10.1084/jem.20142009.

@article{1305252,
   author = {Mansouri, Larry and Sutton, LesleyandAnn and Ljungstrom, Viktor and Bondza, Sina and Arngarden, Linda and Bhoi, Sujata and Larsson, Jimmy and Cortese, Diego and Kalushkova, Antonia and Plevová, Karla and Young, Erin and Gunnarsson, Rebeqa and FalkandSorqvist, Elin and Lonn, Peter and Muggen, Alice F. and Yan, XiaoandJie and Sander, Brigitta and Enblad, Gunilla and Smedby, Karin E. and Juliusson, Gunnar and Belessi, Chrysoula and Rung, Johan and Chiorazzi, Nicholas and Strefford, Jonathan C. and Langerak, Anton W. and Pospíšilová, Šárka and Davi, Frederic and Hellstrom, Mats and JernbergandWiklund, Helena and Ghia, Paolo and Soderberg, Ola and Stamatopoulos, Kostas and Nilsson, Marcus Lars Vittorio and Rosenquist, Richard},
   article_location = {New York},
   article_number = {6},
   doi = {https://doi.org/10.1084/jem.20142009},
   keywords = {CELL LYMPHOMA; MUTATIONS; ACTIVATION; RECEPTORS; PHENOTYPE; PATTERNS; SUBSETS; CANCER},
   language = {eng},
   issn = {0022-1007},
   journal = {The Journal of Experimental Medicine},
   title = {Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia},
   url = {http://jem.rupress.org/content/212/6/830.full.pdf+html},
   volume = {212},
   year = {2015}
}

TY  - JOUR
ID  - 1305252
AU  - 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
PY  - 2015
TI  - Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia
JF  - The Journal of Experimental Medicine
VL  - 212
IS  - 6
SP  - 833-843
EP  - 833-843
PB  - Rockefeller University Press
SN  - 00221007
KW  - CELL LYMPHOMA
KW  - MUTATIONS
KW  - ACTIVATION
KW  - RECEPTORS
KW  - PHENOTYPE
KW  - PATTERNS
KW  - SUBSETS
KW  - CANCER
UR  - http://jem.rupress.org/content/212/6/830.full.pdf+html
L2  - http://jem.rupress.org/content/212/6/830.full.pdf+html
N2  - 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.
ER  -

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 a Richard ROSENQUIST. Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia. \textit{The Journal of Experimental Medicine}. New York: Rockefeller University Press, 2015, roč.~212, č.~6, s.~833-843. ISSN~0022-1007. Dostupné z: https://doi.org/10.1084/jem.20142009.

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