{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:56:24Z","timestamp":1789016184657,"version":"build-2803163510"},"reference-count":58,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,10,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.<\/jats:p>","DOI":"10.1182\/bloodadvances.2023010045","type":"journal-article","created":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T14:34:11Z","timestamp":1688567651000},"page":"6092-6107","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":41,"title":["Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in\n                    <i>RUNX1<\/i>\n                    ,\n                    <i>GATA2<\/i>\n                    , and\n                    <i>DDX41<\/i>"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2847-8586","authenticated-orcid":false,"given":"Claire C.","family":"Homan","sequence":"first","affiliation":[{"name":"1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia"},{"name":"2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8171-4106","authenticated-orcid":false,"given":"Michael W.","family":"Drazer","sequence":"additional","affiliation":[{"name":"3Departments of Medicine and Human Genetics, Section of Hematology\/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yu","sequence":"additional","affiliation":[{"name":"4Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-5830","authenticated-orcid":false,"given":"David M.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia"},{"name":"2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"},{"name":"5ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6821-5401","authenticated-orcid":false,"given":"Jinghua","family":"Feng","sequence":"additional","affiliation":[{"name":"2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"},{"name":"5ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9806-0105","authenticated-orcid":false,"given":"Luis","family":"Arriola-Martinez","sequence":"additional","affiliation":[{"name":"1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia"},{"name":"2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Pozsgai","sequence":"additional","affiliation":[{"name":"3Departments of Medicine and Human Genetics, Section of Hematology\/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8255-6816","authenticated-orcid":false,"given":"Kelsey E.","family":"McNeely","sequence":"additional","affiliation":[{"name":"3Departments of Medicine and Human Genetics, Section of Hematology\/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuong","family":"Ha","sequence":"additional","affiliation":[{"name":"1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia"},{"name":"2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvathy","family":"Venugopal","sequence":"additional","affiliation":[{"name":"1Department of 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