Portal de Periódicos da CAPES

Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

2021; Nature Portfolio; Volume: 27; Issue: 10 Linguagem: Inglês

10.1038/s41591-021-01511-6

1546-170X

Sushree Sangita Sahoo, Victor B. Pastor, Charnise Goodings, Rebecca Voss, Emilia J. Kozyra, Amina Szvetnik, Peter Noellke, Michael Dworzak, Jan Starý, Franco Locatelli, Riccardo Masetti, Markus Schmugge, Barbara De Moerloose, Albert Català, Krisztián Kállay, Dominik Turkiewicz, Henrik Hasle, Jochen Buechner, Kirsi Jahnukainen, Marek Ussowicz, Sophia Polychronopoulou, Owen P. Smith, Oksana Fabri, Shlomit Barzilai, Válerie de Haas, Irith Baumann, Stephan Schwarz‐Furlan, Jan Starý, Barbara De Moerloose, Krisztián Kállay, Owen P. Smith, Válerie de Haas, Gudrun Göhring, Charlotte M. Niemeyer, Karin Nebral, Ingrid Simonitsch-Kluppp, Pascale De Paepe, Nadine Van Roy, Vít Campr, Zuzana Zemanová, Erik Clasen‐Linde, Tine Plesner, Brigitte Schlegelberger, Martina Rudelius, Kalliopi N. Manola, Kalliopi Stefanaki, Judit Csomor, Hajnalka Andrikovics, David R. Betts, Maureen J. O’Sullivan, Yaniv Zohar, Marta Jeison, Rita De Vito, Francesco Pasquali, Jadwiga Małdyk, Olga Haus, Helena Alaiz, Paula Kjöllerström, Luís Mascarenhas‐Lemos, Ivana Boďová, Martin Čermák, Lukáš Plank, Barbara Gazić, Marko Kavčič, Helena Podgornik, Margarita Llavador Ros, José Cervera, Carole Gengler, Joëlle Tchinda, Berna Beverloo, Roos J. Leguit, Marena R. Niewisch, Martin G. Sauer, Birgit Burkhardt, Peter Lang, Peter Bader, Rita Beier, Ingo Müller, Michael H. Albert, Roland Meisel, Ansgar Schulz, Gunnar Cario, Pritam Kumar Panda, Julius Wehrle, Shinsuke Hirabayashi, Marta Derecka, Robert Durruthy-Durruthy, Gudrun Göhring, Ayami Yoshimi‐Noellke, Manching Ku, Dirk Lebrecht, Miriam Erlacher, Christian Flotho, Brigitte Strahm, Charlotte M. Niemeyer, Marcin W. Wlodarski,

Immunodeficiency and Autoimmune Disorders

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. 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.