{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T19:45:55Z","timestamp":1780343155603,"version":"3.54.1"},"reference-count":90,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:00:00Z","timestamp":1657756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"BMBF","doi-asserted-by":"publisher","award":["01GM1911B"],"award-info":[{"award-number":["01GM1911B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and\/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.<\/jats:p>","DOI":"10.3390\/cancers14143431","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T00:17:10Z","timestamp":1657844230000},"page":"3431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Beyond Pathogenic RUNX1 Germline Variants: The Spectrum of Somatic Alterations in RUNX1-Familial Platelet Disorder with Predisposition to Hematologic Malignancies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-8483","authenticated-orcid":false,"given":"Alisa","family":"F\u00f6rster","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Decker","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Schlegelberger","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6470-8612","authenticated-orcid":false,"given":"Tim","family":"Ripperger","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1182\/blood-2016-10-687830","article-title":"Role of RUNX1 in hematological malignancies","volume":"129","author":"Sood","year":"2017","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1093\/nar\/23.14.2762","article-title":"Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia","volume":"23","author":"Miyoshi","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/0168-9525(93)90026-E","article-title":"The Runt domain identifies a new family of heteromeric transcriptional regulators","volume":"9","author":"Kagoshima","year":"1993","journal-title":"Trends Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.1128\/mcb.13.6.3324-3339.1993","article-title":"Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor","volume":"13","author":"Wang","year":"1993","journal-title":"Mol. 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