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

•We describe a novel pathway leading to histiocytosis in which defective nucleoside transport drives hyperactivation of TLR–MAPK signaling.•Patients with the histiocytosis-predisposing genetic disorder H syndrome may benefit from MAPK–directed targeted therapy. [Display omitted] Histiocytoses are in...

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Bibliographic Details
Published in:Blood 2023-11, Vol.142 (20), p.1740-1751
Main Authors: Shiloh, Ruth, Lubin, Ruth, David, Odeya, Geron, Ifat, Okon, Elimelech, Hazan, Idit, Zaliova, Marketa, Amarilyo, Gil, Birger, Yehudit, Borovitz, Yael, Brik, Dafna, Broides, Arnon, Cohen-Kedar, Sarit, Harel, Liora, Kristal, Eyal, Kozlova, Daria, Ling, Galina, Shapira Rootman, Mika, Shefer Averbuch, Noa, Spielman, Shiri, Trka, Jan, Izraeli, Shai, Yona, Simon, Elitzur, Sarah
Format: Article
Language:English
Subjects:
Histiocytosis - genetics
Histiocytosis - pathology
Humans
Inflammation - genetics
Mitogen-Activated Protein Kinases
Mutation
Nucleoside Transport Proteins - genetics
Nucleoside Transport Proteins - metabolism
Toll-Like Receptors
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Summary:•We describe a novel pathway leading to histiocytosis in which defective nucleoside transport drives hyperactivation of TLR–MAPK signaling.•Patients with the histiocytosis-predisposing genetic disorder H syndrome may benefit from MAPK–directed targeted therapy. [Display omitted] 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 germ line 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 ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK 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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2023020714