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.

• 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
• Názvy látek
• GATA2 protein, human MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• nádorové supresorové proteiny MeSH
• SAMD9 protein, human MeSH Prohlížeč
• SAMD9L protein, human MeSH Prohlížeč
• transkripční faktor GATA2 MeSH