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

Ruth Shiloh*, Ruth Lubin, Odeya David, Ifat Geron, Elimelech Okon, Idit Hazan, Marketa Zaliova, Gil Amarilyo, Yehudit Birger, Yael Borovitz, Dafna Brik, Arnon Broides, Sarit Cohen-Kedar, Liora Harel, Eyal Kristal, Daria Kozlova, Galina Ling, Mika Shapira Rootman, Noa Shefer Averbuch, Shiri SpielmanJan Trka, Shai Izraeli, Simon Yona, Sarah Elitzur*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1740-1751
Number of pages12
JournalBlood
Volume142
Issue number20
DOIs
StatePublished - 16 Nov 2023

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