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

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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; Starý, Jan; Locatelli, Franco; Masetti, Riccardo; Schmugge, Markus; De Moerloose, Barbara; Catala, Albert; Kállay, Krisztián; 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; Müller, Ingo; Albert, Michael H; Meisel, Roland; Schulz, Ansgar; Cario, Gunnar; Panda, Pritam K; Wehrle, Julius; Hirabayashi, Shinsuke; Derecka, Marta; Durruthy-Durruthy, Robert; Göhring, Gudrun; Yoshimi-Noellke, Ayami; Ku, Manching; Lebrecht, Dirk; Erlacher, Miriam; Flotho, Christian; Strahm, Brigitte; Niemeyer, Charlotte M; Wlodarski, Marcin W; European Working Group of MDS in Children (EWOG-MDS).

In: NAT MED, Vol. 27, No. 10, 10.2021, p. 1806-1817.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sahoo, SS, Pastor, VB, Goodings, C, Voss, RK, Kozyra, EJ, 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, OP, Fabri, O, Barzilai, S, de Haas, V, Baumann, I, Schwarz-Furlan, S, Niewisch, MR, Sauer, MG, Burkhardt, B, Lang, P, Bader, P, Beier, R, Müller, I, Albert, MH, Meisel, R, Schulz, A, Cario, G, Panda, PK, 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, CM, Wlodarski, MW & European Working Group of MDS in Children (EWOG-MDS) 2021, 'Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes', NAT MED, vol. 27, no. 10, pp. 1806-1817. https://doi.org/10.1038/s41591-021-01511-6

APA

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., ... European Working Group of MDS in Children (EWOG-MDS) (2021). Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. NAT MED, 27(10), 1806-1817. https://doi.org/10.1038/s41591-021-01511-6

Vancouver

Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra EJ, Szvetnik A et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. NAT MED. 2021 Oct;27(10):1806-1817. https://doi.org/10.1038/s41591-021-01511-6

Bibtex

@article{19e869e372d24ce4be8b0380e958922d,
title = "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.",
keywords = "Adolescent, Bone Marrow Cells/metabolism, Child, Child, Preschool, Clonal Evolution/genetics, Clonal Hematopoiesis/genetics, Female, GATA2 Transcription Factor/genetics, Germ-Line Mutation/genetics, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Infant, Intracellular Signaling Peptides and Proteins/genetics, Kaplan-Meier Estimate, Male, Myelodysplastic Syndromes/genetics, Single-Cell Analysis, Tumor Suppressor Proteins/genetics",
author = "Sahoo, {Sushree S} and Pastor, {Victor B} and Charnise Goodings and Voss, {Rebecca K} and Kozyra, {Emilia J} and Amina Szvetnik and Peter Noellke and Michael Dworzak and Jan Star{\'y} and Franco Locatelli and Riccardo Masetti and Markus Schmugge and {De Moerloose}, Barbara and Albert Catala and Kriszti{\'a}n K{\'a}llay and Dominik Turkiewicz and Henrik Hasle and Jochen Buechner and Kirsi Jahnukainen and Marek Ussowicz and Sophia Polychronopoulou and Smith, {Owen P} and Oksana Fabri and Shlomit Barzilai and {de Haas}, Valerie and Irith Baumann and Stephan Schwarz-Furlan and Niewisch, {Marena R} and Sauer, {Martin G} and Birgit Burkhardt and Peter Lang and Peter Bader and Rita Beier and Ingo M{\"u}ller and Albert, {Michael H} and Roland Meisel and Ansgar Schulz and Gunnar Cario and Panda, {Pritam K} and Julius Wehrle and Shinsuke Hirabayashi and Marta Derecka and Robert Durruthy-Durruthy and Gudrun G{\"o}hring and Ayami Yoshimi-Noellke and Manching Ku and Dirk Lebrecht and Miriam Erlacher and Christian Flotho and Brigitte Strahm and Niemeyer, {Charlotte M} and Wlodarski, {Marcin W} and {European Working Group of MDS in Children (EWOG-MDS)}",
note = "{\textcopyright} 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = oct,
doi = "10.1038/s41591-021-01511-6",
language = "English",
volume = "27",
pages = "1806--1817",
journal = "NAT MED",
issn = "1078-8956",
publisher = "NATURE PUBLISHING GROUP",
number = "10",

}

RIS

TY - JOUR

T1 - Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

AU - Sahoo, Sushree S

AU - Pastor, Victor B

AU - Goodings, Charnise

AU - Voss, Rebecca K

AU - Kozyra, Emilia J

AU - Szvetnik, Amina

AU - Noellke, Peter

AU - Dworzak, Michael

AU - Starý, Jan

AU - Locatelli, Franco

AU - Masetti, Riccardo

AU - Schmugge, Markus

AU - De Moerloose, Barbara

AU - Catala, Albert

AU - Kállay, Krisztián

AU - Turkiewicz, Dominik

AU - Hasle, Henrik

AU - Buechner, Jochen

AU - Jahnukainen, Kirsi

AU - Ussowicz, Marek

AU - Polychronopoulou, Sophia

AU - Smith, Owen P

AU - Fabri, Oksana

AU - Barzilai, Shlomit

AU - de Haas, Valerie

AU - Baumann, Irith

AU - Schwarz-Furlan, Stephan

AU - Niewisch, Marena R

AU - Sauer, Martin G

AU - Burkhardt, Birgit

AU - Lang, Peter

AU - Bader, Peter

AU - Beier, Rita

AU - Müller, Ingo

AU - Albert, Michael H

AU - Meisel, Roland

AU - Schulz, Ansgar

AU - Cario, Gunnar

AU - Panda, Pritam K

AU - Wehrle, Julius

AU - Hirabayashi, Shinsuke

AU - Derecka, Marta

AU - Durruthy-Durruthy, Robert

AU - Göhring, Gudrun

AU - Yoshimi-Noellke, Ayami

AU - Ku, Manching

AU - Lebrecht, Dirk

AU - Erlacher, Miriam

AU - Flotho, Christian

AU - Strahm, Brigitte

AU - Niemeyer, Charlotte M

AU - Wlodarski, Marcin W

AU - European Working Group of MDS in Children (EWOG-MDS)

N1 - © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

KW - Adolescent

KW - Bone Marrow Cells/metabolism

KW - Child

KW - Child, Preschool

KW - Clonal Evolution/genetics

KW - Clonal Hematopoiesis/genetics

KW - Female

KW - GATA2 Transcription Factor/genetics

KW - Germ-Line Mutation/genetics

KW - HEK293 Cells

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Infant

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Kaplan-Meier Estimate

KW - Male

KW - Myelodysplastic Syndromes/genetics

KW - Single-Cell Analysis

KW - Tumor Suppressor Proteins/genetics

U2 - 10.1038/s41591-021-01511-6

DO - 10.1038/s41591-021-01511-6

M3 - SCORING: Journal article

C2 - 34621053

VL - 27

SP - 1806

EP - 1817

JO - NAT MED

JF - NAT MED

SN - 1078-8956

IS - 10

ER -