{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:42:41Z","timestamp":1792676561499,"version":"4.5.0"},"reference-count":65,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,11,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1182\/blood.2023020714","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T16:14:24Z","timestamp":1695399264000},"page":"1740-1751","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":23,"title":["Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling"],"prefix":"10.1182","volume":"142","author":[{"given":"Ruth","family":"Shiloh","sequence":"first","affiliation":[{"name":"1The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children\u2019s Medical Center, Petach Tikva, Israel"},{"name":"2Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4077-7968","authenticated-orcid":false,"given":"Ruth","family":"Lubin","sequence":"additional","affiliation":[{"name":"3The Institute of Biomedical and Oral Research, Hebrew University, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odeya","family":"David","sequence":"additional","affiliation":[{"name":"4Pediatric Endocrinology Unit, Soroka University Medical Center, Beer Sheva, Israel"},{"name":"5Pediatric Ambulatory Center, Soroka University Medical Center, Beer Sheva, Israel"},{"name":"6Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifat","family":"Geron","sequence":"additional","affiliation":[{"name":"1The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children\u2019s Medical Center, Petach Tikva, Israel"},{"name":"2Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elimelech","family":"Okon","sequence":"additional","affiliation":[{"name":"7Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idit","family":"Hazan","sequence":"additional","affiliation":[{"name":"3The Institute of Biomedical and Oral Research, Hebrew University, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1639-7124","authenticated-orcid":false,"given":"Marketa","family":"Zaliova","sequence":"additional","affiliation":[{"name":"8Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine of Charles University Prague and University Hospital Motol, Prague, Czech 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Medicine, Tel Aviv University, Tel Aviv, Israel"},{"name":"10Institute of Nephrology, Schneider Children\u2019s Medical Center, Petach Tikva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafna","family":"Brik","sequence":"additional","affiliation":[{"name":"1The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children\u2019s Medical Center, Petach Tikva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Broides","sequence":"additional","affiliation":[{"name":"5Pediatric Ambulatory Center, Soroka University Medical Center, Beer Sheva, Israel"},{"name":"6Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel"},{"name":"11Pediatric Immunology Clinic, Soroka University Medical Center, Beer Sheva, 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Israel"},{"name":"19Beckman Research Institute, City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-2008","authenticated-orcid":false,"given":"Simon","family":"Yona","sequence":"additional","affiliation":[{"name":"3The Institute of Biomedical and Oral Research, Hebrew University, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3495-7578","authenticated-orcid":false,"given":"Sarah","family":"Elitzur","sequence":"additional","affiliation":[{"name":"1The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children\u2019s Medical Center, Petach Tikva, Israel"},{"name":"7Faculty of Medicine, Tel Aviv University, Tel Aviv, 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