作者
Ruth Shiloh,Ruth Lubin,Odeya David,Ifat Geron,Elimelech Okon,Idit Hazan,Markéta Žaliová,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 Spielman,Jan Trka,Shai Izraeli,Simon Yona,Sarah Elitzur
摘要
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.