Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
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Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. / Sahoo, Sushree S; Pastor, Victor B; Goodings, Charnise; Voss, Rebecca K; Kozyra, Emilia J; Szvetnik, Amina; Noellke, Peter; Dworzak, Michael; Starý, Jan; Locatelli, Franco; Masetti, Riccardo; Schmugge, Markus; De Moerloose, Barbara; Catala, Albert; Kállay, Krisztián; Turkiewicz, Dominik; Hasle, Henrik; Buechner, Jochen; Jahnukainen, Kirsi; Ussowicz, Marek; Polychronopoulou, Sophia; Smith, Owen P; Fabri, Oksana; Barzilai, Shlomit; de Haas, Valerie; Baumann, Irith; Schwarz-Furlan, Stephan; Niewisch, Marena R; Sauer, Martin G; Burkhardt, Birgit; Lang, Peter; Bader, Peter; Beier, Rita; Müller, Ingo; Albert, Michael H; Meisel, Roland; Schulz, Ansgar; Cario, Gunnar; Panda, Pritam K; Wehrle, Julius; Hirabayashi, Shinsuke; Derecka, Marta; Durruthy-Durruthy, Robert; Göhring, Gudrun; Yoshimi-Noellke, Ayami; Ku, Manching; Lebrecht, Dirk; Erlacher, Miriam; Flotho, Christian; Strahm, Brigitte; Niemeyer, Charlotte M; Wlodarski, Marcin W; European Working Group of MDS in Children (EWOG-MDS).
in: NAT MED, Jahrgang 27, Nr. 10, 10.2021, S. 1806-1817.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
AU - Sahoo, Sushree S
AU - Pastor, Victor B
AU - Goodings, Charnise
AU - Voss, Rebecca K
AU - Kozyra, Emilia J
AU - Szvetnik, Amina
AU - Noellke, Peter
AU - Dworzak, Michael
AU - Starý, Jan
AU - Locatelli, Franco
AU - Masetti, Riccardo
AU - Schmugge, Markus
AU - De Moerloose, Barbara
AU - Catala, Albert
AU - Kállay, Krisztián
AU - Turkiewicz, Dominik
AU - Hasle, Henrik
AU - Buechner, Jochen
AU - Jahnukainen, Kirsi
AU - Ussowicz, Marek
AU - Polychronopoulou, Sophia
AU - Smith, Owen P
AU - Fabri, Oksana
AU - Barzilai, Shlomit
AU - de Haas, Valerie
AU - Baumann, Irith
AU - Schwarz-Furlan, Stephan
AU - Niewisch, Marena R
AU - Sauer, Martin G
AU - Burkhardt, Birgit
AU - Lang, Peter
AU - Bader, Peter
AU - Beier, Rita
AU - Müller, Ingo
AU - Albert, Michael H
AU - Meisel, Roland
AU - Schulz, Ansgar
AU - Cario, Gunnar
AU - Panda, Pritam K
AU - Wehrle, Julius
AU - Hirabayashi, Shinsuke
AU - Derecka, Marta
AU - Durruthy-Durruthy, Robert
AU - Göhring, Gudrun
AU - Yoshimi-Noellke, Ayami
AU - Ku, Manching
AU - Lebrecht, Dirk
AU - Erlacher, Miriam
AU - Flotho, Christian
AU - Strahm, Brigitte
AU - Niemeyer, Charlotte M
AU - Wlodarski, Marcin W
AU - European Working Group of MDS in Children (EWOG-MDS)
N1 - © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - Adolescent
KW - Bone Marrow Cells/metabolism
KW - Child
KW - Child, Preschool
KW - Clonal Evolution/genetics
KW - Clonal Hematopoiesis/genetics
KW - Female
KW - GATA2 Transcription Factor/genetics
KW - Germ-Line Mutation/genetics
KW - HEK293 Cells
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - Infant
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Kaplan-Meier Estimate
KW - Male
KW - Myelodysplastic Syndromes/genetics
KW - Single-Cell Analysis
KW - Tumor Suppressor Proteins/genetics
U2 - 10.1038/s41591-021-01511-6
DO - 10.1038/s41591-021-01511-6
M3 - SCORING: Journal article
C2 - 34621053
VL - 27
SP - 1806
EP - 1817
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 10
ER -