Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Sahoo SS 

PROVIDER: S-EPMC9330547 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Sahoo Sushree S SS   Pastor Victor B VB   Goodings Charnise C   Voss Rebecca K RK   Kozyra Emilia J EJ   Szvetnik Amina A   Noellke Peter P   Dworzak Michael M   Starý Jan J   Locatelli Franco F   Masetti Riccardo R   Schmugge Markus M   De Moerloose Barbara B   Catala Albert A   Kállay Krisztián K   Turkiewicz Dominik D   Hasle Henrik H   Buechner Jochen J   Jahnukainen Kirsi K   Ussowicz Marek M   Polychronopoulou Sophia S   Smith Owen P OP   Fabri Oksana O   Barzilai Shlomit S   de Haas Valerie V   Baumann Irith I   Schwarz-Furlan Stephan S   Niewisch Marena R MR   Sauer Martin G MG   Burkhardt Birgit B   Lang Peter P   Bader Peter P   Beier Rita R   Müller Ingo I   Albert Michael H MH   Meisel Roland R   Schulz Ansgar A   Cario Gunnar G   Panda Pritam K PK   Wehrle Julius J   Hirabayashi Shinsuke S   Derecka Marta M   Durruthy-Durruthy Robert R   Göhring Gudrun G   Yoshimi-Noellke Ayami A   Ku Manching M   Lebrecht Dirk D   Erlacher Miriam M   Flotho Christian C   Strahm Brigitte B   Niemeyer Charlotte M CM   Wlodarski Marcin W MW  

Nature medicine 20211007 10


Germline SAMD9 and SAMD9L mutations (SAMD9/9L<sup>mut</sup>) 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<sup>mut</sup> accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the co  ...[more]

Similar Datasets

| S-EPMC7388796 | biostudies-literature
| S-EPMC3685527 | biostudies-literature
| S-EPMC6124395 | biostudies-literature
| S-EPMC6251008 | biostudies-literature
| S-EPMC9613457 | biostudies-literature
| S-EPMC5530598 | biostudies-literature
| S-EPMC10438798 | biostudies-literature
| S-EPMC6613757 | biostudies-literature
| S-EPMC9618778 | biostudies-literature
| S-EPMC7891089 | biostudies-literature