Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
Autor: | Sahoo S. S., Pastor V. B., Goodings C., Voss R. K., Kozyra E. J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O. P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B. D., Smith O., Haas V. D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P. D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R. D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L. M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M. L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M. R., Sauer M. G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M. H., Meisel R., Schulz A., Cario G., Panda P. K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C. M., Wlodarski M. W. |
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Přispěvatelé: | Sahoo S.S., Pastor V.B., Goodings C., Voss R.K., Kozyra E.J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O.P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B.D., Smith O., Haas V.D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P.D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R.D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L.M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M.L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M.R., Sauer M.G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M.H., Meisel R., Schulz A., Cario G., Panda P.K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C.M., Wlodarski M.W., Clinical Genetics |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Oncology
Male medicine.medical_specialty Monosomy Adolescent Somatic cell Medizin Bone Marrow Cells Kaplan-Meier Estimate General Biochemistry Genetics and Molecular Biology Germline Article Clonal Evolution Germline mutation SDG 3 - Good Health and Well-being Internal medicine medicine Humans Child Germ-Line Mutation Chromosome 7 (human) Cytopenia clonal hemopoiesis business.industry Myelodysplastic syndromes Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins High-Throughput Nucleotide Sequencing Infant General Medicine medicine.disease GATA2 Transcription Factor SAMD9 and SAMD9L mutations Pediatric Myelodysplastic syndromes medicine.anatomical_structure HEK293 Cells Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA Child Preschool Myelodysplastic Syndromes Female Bone marrow Clonal Hematopoiesis Single-Cell Analysis business |
Zdroj: | Nat Med Nature Medicine, 27(10), 1806-1817. Nature Publishing Group Sahoo, S S, Pastor, V B, Goodings, C, Voss, R K, Kozyra, E J, Szvetnik, A, Noellke, P, Dworzak, M, Starý, J, Locatelli, F, Masetti, R, Schmugge, M, De Moerloose, B, Catala, A, Kállay, K, Turkiewicz, D, Hasle, H, Buechner, J, Jahnukainen, K, Ussowicz, M, Polychronopoulou, S, Smith, O P, Fabri, O, Barzilai, S, de Haas, V, Baumann, I, Schwarz-Furlan, S, Niewisch, M R, Sauer, M G, Burkhardt, B, Lang, P, Bader, P, Beier, R, Müller, I, Albert, M H, Meisel, R, Schulz, A, Cario, G, Panda, P K, Wehrle, J, Hirabayashi, S, Derecka, M, Durruthy-Durruthy, R, Göhring, G, Yoshimi-Noellke, A, Ku, M, Lebrecht, D, Erlacher, M, Flotho, C, Strahm, B, Niemeyer, C M, European Working Group of MDS in Children (EWOG-MDS) & Wlodarski, M W 2021, ' Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes ', Nature Medicine, vol. 27, no. 10, pp. 1806-1817 . https://doi.org/10.1038/s41591-021-01511-6 |
ISSN: | 1078-8956 |
Popis: | 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. |
Databáze: | OpenAIRE |
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