Loss-of-function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling
The result's identifiers
Result code in 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>
Alternative codes found
RIV/00216208:11130/23:10470193
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Loss-of-function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Blood
ISSN
0006-4971
e-ISSN
1528-0020
Volume of the periodical
142
Issue of the periodical within the volume
20
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
1740-1751
UT code for WoS article
001117787100001
EID of the result in the Scopus database
2-s2.0-85174215155