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; Stary, Jan; Locatelli, Franco; Masetti, Riccardo; Schmugge, Markus; De Moerloose, Barbara; Catala, Albert; Kallay, Krisztian; 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; Mueller, Ingo; Albert, Michael H.; Meisel, Roland; Schulz, Ansgar; Cario, Gunnar; Panda, Pritam K.; Wehrle, Julius; Hirabayashi, Shinsuke; Derecka, Marta; Durruthy-Durruthy, Robert; Goehring, Gudrun; Yoshimi-Noellke, Ayami; Ku, Manching; Lebrecht, Dirk; Erlacher, Miriam; Flotho, Christian; Strahm, Brigitte; Niemeyer, Charlotte M. und Wlodarski, Marcin W. (2021): Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. In: Nature Medicine, Bd. 27, Nr. 10: S. 1806-1817

Abstract

This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome. Germline SAMD9 and SAMD9L mutations (SAMD9/9L(mut)) 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 SAMD9/9L(mut) accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L(mut) 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 SAMD9/9L(mut) clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L(mut) suppressed HEK293 cell growth, and mutations expressed in CD34(+) cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L(mut) 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 SAMD9/9L(mut)). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L(mut) MDS and exemplify the exceptional plasticity of hematopoiesis in children.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1078-8956
• Sprache: Englisch