IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F24%3A00079848" target="_blank" >RIV/65269705:_____/24:00079848 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/24:00136209

Výsledek na webu

<a href="https://www.nature.com/articles/s41375-024-02236-4" target="_blank" >https://www.nature.com/articles/s41375-024-02236-4</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41375-024-02236-4" target="_blank" >10.1038/s41375-024-02236-4</a>

Jazyk výsledku

angličtina

Název v původním jazyce

IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

Popis výsledku v původním jazyce

The NFKBIE gene, which encodes the NF-kappa B inhibitor I kappa B epsilon, is mutated in 3-7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-kappa B activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-kappa B activity and disease expansion. We found that I kappa B epsilon loss leads to NF-kappa B pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. I kappa B epsilon deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-kappa B pathway in CLL and paves the way to translate these findings into novel therapeutic options.

Název v anglickém jazyce

IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

Popis výsledku anglicky

The NFKBIE gene, which encodes the NF-kappa B inhibitor I kappa B epsilon, is mutated in 3-7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-kappa B activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-kappa B activity and disease expansion. We found that I kappa B epsilon loss leads to NF-kappa B pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. I kappa B epsilon deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-kappa B pathway in CLL and paves the way to translate these findings into novel therapeutic options.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Leukemia

ISSN

0887-6924

e-ISSN

1476-5551

Svazek periodika

38

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

1287-1298

Kód UT WoS článku

001197088700001

EID výsledku v databázi Scopus

2-s2.0-85189466933