{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:56:23Z","timestamp":1786470983171,"version":"build-2736575974"},"reference-count":29,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL156866"],"award-info":[{"award-number":["HL156866"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL164825"],"award-info":[{"award-number":["HL164825"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2026,7]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Kaposiform lymphangiomatosis (KLA) is an aggressive complex lymphatic anomaly. Patients exhibit malformed lymphatic vessels and often develop hemorrhagic effusions and elevated angiopoietin\u20102 (Ang\u20102) levels. A somatic NRAS p.Q61R (NRAS\n Q61R<\/jats:sup>\n ) mutation has been associated with KLA. Existing preclinical models do not recapitulate the thoracic effusions that drive morbidity and mortality in patients. The goal of this study was to develop a genetic mouse model that more closely mimics the clinical phenotype of KLA.\n <\/jats:p>\n <\/jats:sec>\n \n Procedure<\/jats:title>\n \n A tamoxifen\u2010inducible Cre\u2010loxP system was used to conditionally express NRAS\n Q61R<\/jats:sup>\n in lymphatic endothelial cells in postnatal mice. Prox1\u2010CreERT2 mice were mated to Lox\u2010STOP\u2010Lox\u2010NRAS\n Q61R<\/jats:sup>\n mice. Tamoxifen (100 or 75\u00a0\u00b5g) was administered to litters on postnatal days (P) 1\u20133 to induce Cre\u2010mediated recombination and NRAS\n Q61R<\/jats:sup>\n expression. Survival, effusion incidence, and plasma Ang\u20102 levels were assessed at 3\u00a0weeks. Recombination efficiency and lymphatic vessel structure in the lungs and whole\u2010mounts of the diaphragm and ear were determined.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n NRAS\n Q61R<\/jats:sup>\n mice treated with 100\u00a0\u00b5g tamoxifen P1\u2013P3 died within 5\u00a0weeks. NRAS\n Q61R<\/jats:sup>\n mice treated with 75\u00a0\u00b5g tamoxifen P1\u2013P3 had increased mortality, severe hemorrhagic and chylous effusions, and approximately three\u2010fold higher angiopoietin\u20102 levels. NRAS\n Q61R<\/jats:sup>\n recombination was 93% in the pulmonary lymphatics, which were enlarged and abnormal. Lymphatic vessel diameters were increased in the diaphragm (193%) and ears (152%).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n NRAS\n Q61R<\/jats:sup>\n mutant mice closely resemble KLA patients with high mortality, hemorrhagic chylothorax, elevated Ang\u20102 levels, and enlarged lymphatic vessels. Future studies can utilize this model to elucidate the mechanisms underlying KLA pathogenesis and test novel therapeutics.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/1545-5017.70339","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T06:14:36Z","timestamp":1776406476000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NRAS\n Q61R<\/sup>\n Expression in Lymphatic Endothelial Cells Causes Enlarged Vessels, Hemorrhagic Chylous Effusions, and High Mortality in a Mouse Model of Kaposiform Lymphangiomatosis"],"prefix":"10.1002","volume":"73","author":[{"given":"C. Griffin","family":"McDaniel","sequence":"first","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Pastura","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua P.","family":"Scallan","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology Morsani School of Medicine University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy D.","family":"Le Cras","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, 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