{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:20:13Z","timestamp":1790914813420,"version":"4.1.0"},"reference-count":18,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T00:00:00Z","timestamp":1686528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2020\u201001902"],"award-info":[{"award-number":["2020\u201001902"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes & Cancer"],"published-print":{"date-parts":[[2023,11]]},"abstract":"Abstract<\/jats:title>Germline RUNX1<\/jats:italic> mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1<\/jats:italic> mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1<\/jats:italic>R204*<\/jats:sup> variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1<\/jats:italic> mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS\u2010RS), classified as a low\u2010risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1<\/jats:italic> gene. While the three main RUNX1\u00a0isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1<\/jats:italic> transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1<\/jats:italic>R204*<\/jats:sup> variant, and has FPDMM but no MM. We demonstrate a RUNX1a<\/jats:italic> increase in MDS\u2010RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b<\/jats:italic> and \u2010c<\/jats:italic> in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1<\/jats:italic> isoform disequilibrium as a mechanism for development of MM.<\/jats:p>","DOI":"10.1002\/gcc.23184","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T07:41:17Z","timestamp":1686555677000},"page":"672-677","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The clinical phenotype of germline RUNX1<\/i><\/scp> mutations in relation to the accompanying somatic variants and RUNX1<\/i><\/scp> isoform expression"],"prefix":"10.1002","volume":"62","author":[{"given":"David","family":"Cabrerizo Granados","sequence":"first","affiliation":[{"name":"Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indira","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Baliakas","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Hellstr\u00f6m\u2010Lindberg","sequence":"additional","affiliation":[{"name":"Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2335-3370","authenticated-orcid":false,"given":"Vanessa","family":"Lundin","sequence":"additional","affiliation":[{"name":"Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-013-1347-3"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/16078454.2020.1858598"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003357"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.248955"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-08-518886"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.31.1175"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005814"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.812639"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0040172"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2022.2067997"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2016002725"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022017619"},{"issue":"6","key":"e_1_2_9_14_1","article-title":"Nordic guidelines for germline predisposition to myeloid neoplasms in adults: recommendations for genetic diagnosis, clinical management and follow\u2010up","volume":"3","author":"Baliakas P","year":"2019","journal-title":"Hema"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.278762"},{"key":"e_1_2_9_16_1","volume-title":"International Agency for Research on C, World Health O. WHO classification of tumours of haematopoietic and lymphoid tissues","author":"Swerdlow SH","year":"2017"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0816-y"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2200008"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001127"}],"container-title":["Genes, Chromosomes and Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gcc.23184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T12:17:44Z","timestamp":1695125864000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gcc.23184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,12]]},"references-count":18,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/gcc.23184"],"URL":"https:\/\/doi.org\/10.1002\/gcc.23184","archive":["Portico"],"relation":{},"ISSN":["1045-2257","1098-2264"],"issn-type":[{"value":"1045-2257","type":"print"},{"value":"1098-2264","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,12]]},"assertion":[{"value":"2023-03-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}