{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:58:43Z","timestamp":1787752723121,"version":"build-2784847793"},"reference-count":42,"publisher":"American Society for Clinical Investigation","issue":"2","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":58,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["7P01HL158688"],"award-info":[{"award-number":["7P01HL158688"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK124115"],"award-info":[{"award-number":["R01DK124115"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,16]]},"abstract":"<jats:p>\n                    Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in\n                    <jats:italic>ELANE<\/jats:italic>\n                    , the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony\u2013stimulating factor (G-CSF) is a first-line treatment of\n                    <jats:italic>ELANE<\/jats:italic>\n                    -mutant (\n                    <jats:italic>ELANE<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    ) SCN. However, some\n                    <jats:italic>ELANE<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    patients, including patients with\n                    <jats:italic>ELANE<\/jats:italic>\n                    start codon mutations, do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that\n                    <jats:italic>ELANE<\/jats:italic>\n                    start codon mutations suffice to induce G-CSF\u2013resistant granulocytic precursor cell death and refractory SCN.\n                    <jats:italic>ELANE<\/jats:italic>\n                    start codon\u2013mutated neutrophil precursors express predominantly nuclear N-terminally truncated alternate NE. Unlike G-CSF\u2013sensitive\n                    <jats:italic>ELANE<\/jats:italic>\n                    mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the\n                    <jats:italic>ELANE<\/jats:italic>\n                    translation initiation codon resulted in NE aggregates and activated proapoptotic aggrephagy, as determined by downregulated BAG1 expression, decreased BAG1\/BAG3 ratio, NE colocalization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight into G-CSF\u2013resistant\n                    <jats:italic>ELANE<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    SCN, revealing targets for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1172\/jci177342","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T12:00:20Z","timestamp":1732017620000},"source":"Crossref","is-referenced-by-count":3,"title":["G-CSF resistance of ELANE-mutant neutropenia depends on SERF1-containing truncated\u2013neutrophil elastase aggregates"],"prefix":"10.1172","volume":"135","author":[{"given":"Ramesh C.","family":"Nayak","sequence":"first","affiliation":[{"name":"Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Emberesh","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa R.","family":"Trump","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Wellendorf","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek K.","family":"Singh","sequence":"additional","affiliation":[{"name":"Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Korkmaz","sequence":"additional","affiliation":[{"name":"INSERM UMR-1100, Research Center for Respiratory Diseases, and University of Tours, Tours, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall S.","family":"Horwitz","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathology, University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5528-4405","authenticated-orcid":true,"given":"Kasiani C.","family":"Myers","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-9686","authenticated-orcid":true,"given":"Theodosia A.","family":"Kalfa","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Lutzko","sequence":"additional","affiliation":[{"name":"Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."},{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Cancelas","sequence":"additional","affiliation":[{"name":"Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."},{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."},{"name":"Connell and O\u2019Reilly Families Cell Manipulation Core Facility & Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2004.1.63"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2012.10.004"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.7.2317"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/70544"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198906153202402"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22308"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23018"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/petr.13078"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-4370"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80924"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-311704"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-513242"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.221804"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1592\/phco.27.10.1387"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2010.203"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-95611-5"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41144-6"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1001-e237"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/86236"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.7.4613"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1803130115"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.29"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4161\/auto.29409"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nature05291"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.02.010"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.07.020"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1913316116"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.04.031"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.11.014"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2011.01601.x"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-00956-4"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-05-1372"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.12.015"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3577"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2174\/092986710790514480"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2010.15"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217039110"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.083873"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.04963.x"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nm1474"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.05.006"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.001"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/177342\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:47:37Z","timestamp":1779230857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/177342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1,16]]},"published-print":{"date-parts":[[2025,1,16]]}},"alternative-id":["10.1172\/JCI177342"],"URL":"https:\/\/doi.org\/10.1172\/jci177342","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,19]]},"article-number":"e177342"}}