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Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromesSahoo, Sushree S ...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.Source: Nature medicine. - ISSN 1078-8956 (Vol. 27, iss. 10, 2021, str. 1806-1817)Type of material - article, component part ; adult, seriousPublish date - 2021Language - englishCOBISS.SI-ID - 189208323
Author
Sahoo, Sushree S |
Pastor, Victor B |
Goodings, Charnise |
Voss, Rebecca K |
Kozyra, Emilia J |
Szvetnik, Amina |
Noellke, Peter |
Dworzak, Michael N. |
Stary, Jan |
Locatelli, Franco
Other authors
Gazić, Barbara |
Kavčič, Marko, medicina |
Podgornik, Helena
Topics
MDS predisposition |
SAMD9 |
SAMD9L |
somatic genetic rescue |
nagnjenost k MDS |
somatsko genetsko reševanje
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Sahoo, Sushree S | ![]() |
Pastor, Victor B | ![]() |
Goodings, Charnise | ![]() |
Voss, Rebecca K | ![]() |
Kozyra, Emilia J | ![]() |
Szvetnik, Amina | ![]() |
Noellke, Peter | ![]() |
Dworzak, Michael N. | ![]() |
Stary, Jan | ![]() |
Locatelli, Franco | ![]() |
Gazić, Barbara | 20050 |
Kavčič, Marko, medicina | 32049 |
Podgornik, Helena | 12684 |
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