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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F21%3A10432535" target="_blank" >RIV/00064203:_____/21:10432535 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/21:10432535

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=w3cuS4r1O1" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=w3cuS4r1O1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41591-021-01511-6" target="_blank" >10.1038/s41591-021-01511-6</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Medicine

ISSN

1078-8956

e-ISSN

—

Svazek periodika

27

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

1806-1817

Kód UT WoS článku

000704942800003

EID výsledku v databázi Scopus

2-s2.0-85116777637