{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:53:06Z","timestamp":1775886786403,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T00:00:00Z","timestamp":1643673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["PCEFP3_181357"],"award-info":[{"award-number":["PCEFP3_181357"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013904","name":"Swiss BRIDGE Foundation","doi-asserted-by":"publisher","award":["PSB-4066-06-2016"],"award-info":[{"award-number":["PSB-4066-06-2016"]}],"id":[{"id":"10.13039\/501100013904","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer League Basel and the \u201cStiftung f\u00fcr krebskranke Kinder Regio Basiliensis\u201d","award":["KLbB-4784-02-2019"],"award-info":[{"award-number":["KLbB-4784-02-2019"]}]},{"name":"Foundation for the Fight against Cancer","award":["-"],"award-info":[{"award-number":["-"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NHLBI R01 HL157147-01"],"award-info":[{"award-number":["NHLBI R01 HL157147-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Concern Foundation Conquer Cancer Now Award","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal CSF3R mutations such as T618I as driver mutations, but the significance of truncating mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-occurring germline and somatic CSF3R mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair follicle. To investigate a potential predisposition for CNL development and progression by germline CSF3R-W791*, allelic localizations were evaluated. We detected a somatic CSF3R-T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a CSF3R-W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed CSF3R-T618I and W791* on the same allele. A concomitant ASXL1 mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the CSF3R double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a RUNX1 mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a CSF3R-W791* mutation in the germline and acquisition of CSF3R-T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating RUNX1-related clonal transformation.<\/jats:p>","DOI":"10.3390\/curroncol29020068","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T09:59:21Z","timestamp":1643709561000},"page":"805-815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia"],"prefix":"10.3390","volume":"29","author":[{"given":"Franziska C.","family":"Adam","sequence":"first","affiliation":[{"name":"Division of Hematology, University Hospital Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakub","family":"Szybinski","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel and University of Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-1956","authenticated-orcid":false,"given":"J\u00f6rg P.","family":"Halter","sequence":"additional","affiliation":[{"name":"Division of Hematology, University Hospital Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Cantoni","sequence":"additional","affiliation":[{"name":"Kantonsspital Aarau, CH-5001 Aarau, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedel","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Pathology, University Hospital Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4004-3473","authenticated-orcid":false,"given":"Katharina","family":"Leonards","sequence":"additional","affiliation":[{"name":"Division of Hematology, University Hospital Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sime","family":"Brkic","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel and University of Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7092-3351","authenticated-orcid":false,"given":"Jakob R.","family":"Passweg","sequence":"additional","affiliation":[{"name":"Division of Hematology, University Hospital Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivo","family":"Touw","sequence":"additional","affiliation":[{"name":"Department of Hematology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia E.","family":"Maxson","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara C.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Division of Hematology, University Hospital Basel, CH-4031 Basel, Switzerland"},{"name":"Department of Biomedicine, University Hospital Basel and University of Basel, CH-4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/ajh.25688","article-title":"Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management","volume":"95","author":"Szuber","year":"2020","journal-title":"Am. 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Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1182\/blood-2013-06-509976","article-title":"The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition","volume":"122","author":"Fleischman","year":"2013","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1200\/JCO.19.00895","article-title":"Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia","volume":"38","author":"Dao","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1084\/jem.20090693","article-title":"An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia","volume":"206","author":"Plo","year":"2009","journal-title":"J. Exp. 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Case Stud."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/2\/68\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:12:42Z","timestamp":1760134362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/2\/68"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,1]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["curroncol29020068"],"URL":"https:\/\/doi.org\/10.3390\/curroncol29020068","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,1]]}}}