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Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
SS. Sahoo, VB. Pastor, C. Goodings, RK. Voss, EJ. Kozyra, A. Szvetnik, P. Noellke, M. Dworzak, J. Starý, F. Locatelli, R. Masetti, M. Schmugge, B. De Moerloose, A. Catala, K. Kállay, D. Turkiewicz, H. Hasle, J. Buechner, K. Jahnukainen, M....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
NLK
ProQuest Central
od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 2000-01-01 do Před 1 rokem
- MeSH
- analýza jednotlivých buněk MeSH
- buňky kostní dřeně metabolismus MeSH
- dítě MeSH
- HEK293 buňky MeSH
- intracelulární signální peptidy a proteiny genetika MeSH
- Kaplanův-Meierův odhad MeSH
- klonální evoluce genetika MeSH
- klonální hematopoéza genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy genetika patologie MeSH
- nádorové supresorové proteiny genetika MeSH
- předškolní dítě MeSH
- transkripční faktor GATA2 genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.
Department of Hematology and Oncology Hospital Sant Joan de Deu Barcelona Spain
Department of Hematology and Oncology University Children's Hospital Zurich Switzerland
Department of Hematology St Jude Children's Research Hospital Memphis TN USA
Department of Human Genetics Hannover Medical School Hannover Germany
Department of Paediatric Haematology Oncology Ghent University Hospital Ghent Ghent Belgium
Department of Pediatric Haematology Oncology Children's Health Ireland at Crumlin Dublin Ireland
Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Germany
Department of Pediatric Hematology and Oncology Oslo University Hospital Oslo Norway
Department of Pediatric Hematology Oncology Aghia Sophia Children's Hospital Athens Greece
Department of Pediatric Oncology Hematology Skåne University Hospital Lund Sweden
Department of Pediatrics Aarhus University Hospital Aarhus Denmark
Department of Pediatrics University Hospital Schleswig Holstein Campus Kiel Kiel Germany
Department of Pediatrics University Medical Center Ulm Ulm Germany
Dutch Childhood Oncology Group Princess Máxima Center for Pediatric Oncology Utrecht Netherlands
Faculty of Biology University of Freiburg Freiburg Germany
German Cancer Consortium Heidelberg and Freiburg Germany
Institute of Digitalization in Medicine Faculty of Medicine University of Freiburg Freiburg Germany
Institute of Pathology Klinikum Kaufbeuren Ravensburg Kaufbeuren Germany
Institute of Pathology University Hospital Erlangen Erlangen Germany
Mission Bio Inc South San Francisco CA USA
Paediatric Oncology and Haematology IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy
Pediatric Hematology and Oncology University Hospital Muenster Muenster Germany
University Hospital Essen Pediatric Haematology and Oncology Essen Germany
Citace poskytuje Crossref.org
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- $a Sahoo, Sushree S $u Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA $u Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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- $a Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes / $c SS. Sahoo, VB. Pastor, C. Goodings, RK. Voss, EJ. Kozyra, A. Szvetnik, P. Noellke, M. Dworzak, J. Starý, F. Locatelli, R. Masetti, M. Schmugge, B. De Moerloose, A. Catala, K. Kállay, D. Turkiewicz, H. Hasle, J. Buechner, K. Jahnukainen, M. Ussowicz, S. Polychronopoulou, OP. Smith, O. Fabri, S. Barzilai, V. de Haas, I. Baumann, S. Schwarz-Furlan, European Working Group of MDS in Children (EWOG-MDS), MR. Niewisch, MG. Sauer, B. Burkhardt, P. Lang, P. Bader, R. Beier, I. Müller, MH. Albert, R. Meisel, A. Schulz, G. Cario, PK. Panda, J. Wehrle, S. Hirabayashi, M. Derecka, R. Durruthy-Durruthy, G. Göhring, A. Yoshimi-Noellke, M. Ku, D. Lebrecht, M. Erlacher, C. Flotho, B. Strahm, CM. Niemeyer, MW. Wlodarski
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