Loss-of-function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F23%3A10470193" target="_blank" >RIV/00064203:_____/23:10470193 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/23:10470193

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=z3.~UCaNT_" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=z3.~UCaNT_</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood.2023020714" target="_blank" >10.1182/blood.2023020714</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Loss-of-function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

Popis výsledku v původním jazyce

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germline loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss-of-function of SLC29A3 activates nucleoside-sensing Toll-like receptors and downstream MEK-ERK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Název v anglickém jazyce

Loss-of-function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

Popis výsledku anglicky

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germline loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss-of-function of SLC29A3 activates nucleoside-sensing Toll-like receptors and downstream MEK-ERK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Blood

ISSN

0006-4971

e-ISSN

1528-0020

Svazek periodika

142

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

1740-1751

Kód UT WoS článku

001117787100001

EID výsledku v databázi Scopus

2-s2.0-85174215155