ArticleBlood advances2023
Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.
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Article in Blood advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
10.8field-weighted citation impact, top 1% of its field
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Who cites it
31 citing papers in PubMed, 37 citations in OpenAlex.
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- Hematologic malignancies in pediatric patients with RUNX1-familial platelet disorder with associated myeloid malignancy.Blood advances · 2026Observational
- Clinical relevance of mosaic variants detected by exome sequencing.The Journal of allergy and clinical immunology · 2026Article
- Clonal hematopoiesis and its progression to myeloid neoplasms: insights into risk, biology, and therapeutic strategies.Haematologica · 2026Review
- Reframing-renaming(?)-myelodysplastic syndromes/neoplasms and clonal hematopoiesis of indeterminate potential.Leukemia · 2026Review
- Targeting RUNX1 Germline Variants: Agents Under Investigation.Current hematologic malignancy reports · 2025Review
- How to Read a Next-Generation Sequencing Report for AML and MDS? What Hematologists Need to Know.Journal of clinical medicine · 2025Review
- The Dual Role of RUNX1 in Inflammation-Driven Age-Related Diseases: From Molecular Mechanisms to Clinical Translation.Biomedicines · 2025Review
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- Myelodysplastic syndromes: Updates on Genomic Landscape, Molecular Subtypes, & Targeted Therapies.Current hematologic malignancy reports · 2025Review
- Genomic variation in DDX41 identified through clinical sequencing.British journal of haematology · 2025Article
- Germline and somatic genetic landscape of pediatric myelodysplastic syndromes.Haematologica · 2025Review
- Article
- Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective.Genes · 2025Review
- Prevalence of cytopenia(s) and somatic variants in patients with DDX41 mutant germline predisposition syndrome.British journal of haematology · 2025Article
- Genome sequencing in the management of myelodysplastic syndromes and related disorders.Haematologica · 2025Review
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- Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.Annual review of pathology · 2025Review
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Authors and funding
66 authors at 20 institutions in 11 countries.
Claire C HomanDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0003-2847-8586
Michael W DrazerDepartments 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.ORCID 0000-0002-8171-4106
Kai YuDivision of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
David M LawrenceDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0001-5464-5830
Jinghua FengUniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.ORCID 0000-0001-6821-5401
Luis Arriola-MartinezDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0001-9806-0105
Matthew J PozsgaiDepartments 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.
Kelsey E McNeelyDepartments 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.ORCID 0000-0002-8255-6816
Thuong HaDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
Parvathy VenugopalDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
Peer ArtsDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0002-6742-6239
Sarah L King-SmithDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
Jesse CheahDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
Mark ArmstrongDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0002-7974-0137
Paul WangUniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.ORCID 0000-0003-4597-6616
Csaba BödörHCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Alan B CantorDivision of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Mario CazzolaDepartment of Molecular Medicine, University of Pavia, Pavia, Italy.ORCID 0000-0001-6984-8817
Erin DegelmanAlberta Children's Hospital, Calgary, Alberta, Canada.
Courtney D DiNardoDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.ORCID 0000-0001-9003-0390
Nicolas DuployezLaboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France.ORCID 0000-0002-3927-1022
Remi FavierAssistance Publique-Hôpitaux de Paris, Armand Trousseau Children's Hospital, Paris, France.
Stefan FröhlingDepartment of Translational Medical Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ana Rio-MachinCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Jeffery M KlcoSt Jude Children's Research Hospital, Memphis, TN.
Alwin KrämerClinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Mineo KurokawaDepartment of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-4034-2422
Joanne LeeDepartment of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
Luca MalcovatiDepartment of Molecular Medicine, University of Pavia, Pavia, Italy.ORCID 0000-0002-1460-1611
Neil V MorganInstitute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.ORCID 0000-0001-6433-5692
Georges NatsoulisImago Biosciences, Inc, San Francisco, CA.
Carolyn OwenDivision of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada.
Keyur P PatelDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.ORCID 0000-0001-5081-2427
Claude PreudhommeLaboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France.ORCID 0000-0002-1267-9546
Hana RaslovaInstitut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.ORCID 0000-0001-8846-5299
Hugh RienhoffImago Biosciences, Inc, San Francisco, CA.ORCID 0000-0002-0710-0800
Tim RippergerDepartment of Human Genetics, Hannover Medical School, Hannover, Germany.ORCID 0000-0001-6470-8612
Rachael SchulteDivision of Pediatric Hematology and Oncology, Riley Children's Hospital, Indiana University School of Medicine, Indianapolis, IN.
Kiran TawanaDepartment of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom.
Elvira VellosoService of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Benedict YanDepartment of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
Erika KimNational Cancer Institute, National Institutes of Health, Rockville, MD.
Raman SoodDivision of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.ORCID 0000-0001-5565-662X
Amy P HsuNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0001-6841-2122
Steven M HollandNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Kerry PhillipsAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
Nicola K PoplawskiAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
Milena BabicDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
Andrew H WeiDepartment of Haematology, Peter McCallum Cancer Centre, Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Melbourne, VIC, Australia.ORCID 0000-0002-7514-3298
Cecily ForsythCentral Coast Haematology, North Gosford, NSW, Australia.ORCID 0000-0002-9108-3088
Helen Mar FanDepartment of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Ian D LewisAdelaide Oncology & Haematology, North Adelaide, SA, Australia.
Julian CooneyDepartment of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia.
Rachel SusmanGenetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
Lucy C FoxPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Piers BlomberyPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Deepak SinghalDepartment of Haematology, SA Pathology, Adelaide, SA, Australia.ORCID 0000-0002-2024-2969
Devendra HiwaseAdelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
Belinda PhipsonBioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Andreas W SchreiberUniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.ORCID 0000-0002-9081-3405
Christopher N HahnDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0001-5105-2554
Hamish S ScottDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0002-5813-631X
Paul LiuDivision of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Lucy A GodleyDepartments 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.
Anna L BrownDepartment of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.ORCID 0000-0002-9023-0138
NISC Comparative Sequencing Program
South Australia Pathology · AUNational Institutes of Health · USUniversity of Chicago · USGerman Cancer Research Center · DEInserm · FRNational University Cancer Institute, Singapore · SGPeter MacCallum Cancer Centre · AURoyal Adelaide Hospital · AUThe University of Texas MD Anderson Cancer Center · USUniversity of Pavia · ITAddenbrooke's Hospital · GBAlberta Children's Hospital · CAAssistance Publique – Hôpitaux de Paris · FRBoston Children's Hospital · USFiona Stanley Hospital · AUFoothills Medical Centre · CAGosford Hospital · AUMedizinische Hochschule Hannover · DEQueen Mary University of London · GBRiley Hospital for Children · US
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
Indexed as
Hematologic NeoplasmsLeukemiaCarcinogenesisCore Binding Factor Alpha 2 SubunitDEAD-box RNA HelicasesGATA2 Transcription FactorGerm CellsGerm-Line MutationHumansCore Binding Factor Alpha 2 SubunitDDX41 protein, humanDEAD-box RNA HelicasesGATA2 protein, humanGATA2 Transcription FactorRUNX1 protein, human
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