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Clinical evolution,...
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Sahoo, S.Albert-Ludwigs University Freiburg,St Jude Children´s Research Hospital, Memphis
(författare)
Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
- Artikel/kapitelEngelska2021
Förlag, utgivningsår, omfång ...
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2021-10-07
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Springer Science and Business Media LLC,2021
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12 s.
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:1174d29c-ad91-4154-ba8e-f97f9ca86d91
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https://lup.lub.lu.se/record/1174d29c-ad91-4154-ba8e-f97f9ca86d91URI
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https://doi.org/10.1038/s41591-021-01511-6DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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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. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Turkiewicz, DominikLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)do8070tu
(författare)
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Wlodarski, Marcin W.Albert-Ludwigs University Freiburg,St Jude Children´s Research Hospital, Memphis
(författare)
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Albert-Ludwigs University FreiburgSt Jude Children´s Research Hospital, Memphis
(creator_code:org_t)
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et al.
Sammanhörande titlar
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Ingår i:Nature Medicine: Springer Science and Business Media LLC27:10, s. 1806-18171546-170X1078-8956
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