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.
Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes / Sahoo S.S.; Pastor V.B.; Goodings C.; Voss R.K.; Kozyra E.J.; Szvetnik A.; Noellke P.; Dworzak M.; Stary J.; Locatelli F.; Masetti R.; Schmugge M.; De Moerloose B.; Catala A.; Kallay K.; Turkiewicz D.; Hasle H.; Buechner J.; Jahnukainen K.; Ussowicz M.; Polychronopoulou S.; Smith O.P.; Fabri O.; Barzilai S.; de Haas V.; Baumann I.; Schwarz-Furlan S.; Stary J.; Moerloose B.D.; Kallay K.; Smith O.; Haas V.D.; Gohring G.; Niemeyer C.; Nebral K.; Simonitsch-Kluppp I.; Paepe P.D.; Van Roy N.; Campr V.; Zemanova Z.; Clasen-Linde E.; Plesner T.; Schlegelberger B.; Rudelius M.; Manola K.; Stefanaki K.; Csomor J.; Andrikovics H.; Betts D.; O'Sullivan M.; Zohar Y.; Jeison M.; Vito R.D.; Pasquali F.; Maldyk J.; Haus O.; Alaiz H.; Kjollerstrom P.; Lemos L.M.; Bodova I.; Cermak M.; Plank L.; Gazic B.; Kavcic M.; Podgornik H.; Ros M.L.; Cervera J.; Gengler C.; Tchinda J.; Beverloo B.; Leguit R.; Niewisch M.R.; Sauer M.G.; Burkhardt B.; Lang P.; Bader P.; Beier R.; Muller I.; Albert M.H.; Meisel R.; Schulz A.; Cario G.; Panda P.K.; Wehrle J.; Hirabayashi S.; Derecka M.; Durruthy-Durruthy R.; Gohring G.; Yoshimi-Noellke A.; Ku M.; Lebrecht D.; Erlacher M.; Flotho C.; Strahm B.; Niemeyer C.M.; Wlodarski M.W.. - In: NATURE MEDICINE. - ISSN 1078-8956. - ELETTRONICO. - 27:10(2021), pp. 1806-1817. [10.1038/s41591-021-01511-6]
Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
Masetti R.;
2021
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
