clonal
Dotaz
Zobrazit nápovědu
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.
- MeSH
- analýza jednotlivých buněk MeSH
- buňky kostní dřeně metabolismus MeSH
- dítě MeSH
- HEK293 buňky MeSH
- intracelulární signální peptidy a proteiny genetika MeSH
- Kaplanův-Meierův odhad MeSH
- klonální evoluce genetika MeSH
- klonální hematopoéza genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy genetika patologie MeSH
- nádorové supresorové proteiny genetika MeSH
- předškolní dítě MeSH
- transkripční faktor GATA2 genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Klonální hematopoéza neurčitého potenciálu (clonal hematopoiesis of indeterminate potential; CHIP) nástává během stárnutí lidského organizmu postupnou kumulací somatických a potenciálně preleukemických mutací v hematopoetických kmenových buňkách. Tyto mutace se vyskytují v genech, které mimo jiné hrají důležitou roli v regulaci zánětu. Riziko hematologické malignity u nositelů CHIP mutací je relativně nízké. U těchto pacientů se však vyskytuje 40% riziko celkové mortality způsobené vyšším výskytem infarktu myokardu a CMP. Ačkoli v současnosti přibývají důkazy o vztahu mezi CHIP, zánětem a kardiovaskulárními chorobami, vztah mezi CHIP a CMP dosud nebyl zcela objasněn. Cílem tohoto přehledného referátu je poukázat na aktuální a potenciálně klinicky relevatní problematiku, která je nepochybně výchozí pro další výzkum.
Clonal hematopoiesis of indeterminate potential (CHIP) occurs during human aging through the progressive accumulation of somatic and potentially preleukemic mutations in hematopoietic stem cells. These mutations occur in genes that, among other things, play an important role in the regulation of inflammation. The risk of hematological malignancy in carriers of CHIP mutations is relatively low. However, these patients have a 40% risk of all-cause mortality due to a higher incidence of myocardial infarction and stroke. Although there is recent evidence of a relationship between CHIP, inflammation and cardiovascular diseases, the relationship between CHIP and stroke has not yet been fully elucidated. The aim of this review is to highlight a timely and potentially clinically relevant issue that is undoubtedly a starting point for further research.
- MeSH
- ateroskleróza etiologie genetika komplikace MeSH
- cévní mozková příhoda * etiologie genetika komplikace MeSH
- kardiovaskulární nemoci etiologie genetika komplikace MeSH
- klinická studie jako téma MeSH
- klonální hematopoéza * genetika MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- buněčné klony MeSH
- kultivované buňky MeSH
- lymfom MeSH
- myši MeSH
- protinádorové látky MeSH
- techniky in vitro MeSH
- Check Tag
- myši MeSH
Myeloid sarcoma (MS) is a mass-forming extramedullary manifestation of myeloid blasts, either in relation to an underlying acute myeloid leukemia (AML), another myeloid neoplasm (MN) or as a de novo occurrence. Data on the genetic profile of MS are sparse. In this study, 41 MS of 34 patients, including 7 de novo cases and 24 patients with antecedent or synchronous MN, were analyzed with targeted next-generation sequencing (NGS), RNA-based fusion detection, and gene expression profiling (GEP). In 10 patients, a MS developed after stem cell transplantation for MN. Additionally, 21 available pre-transplant bone marrow biopsies (BMB) from 20 patients and 6 post-transplant BMB from 6 patients were investigated. The most frequently mutated gene was TET2 (41%), followed by NPM1 (38%) and NRAS (35%). Overall, 74% of the cases exhibited mutations affecting the MAPK/ERK pathway. AML-type fusions were detected in seven MS patients, who were younger than those without fusions (median 49 versus 67 years). Nine of 13 patients with a MN and available pre-transplant BMB showed additional mutations restricted to the MS, including an additional NRAS mutation in 3/5 cases with AML. Five of seven of patients with pre-transplant BMB without evidence of a MN revealed clonal hematopoiesis (CH), mostly shared TET2 mutations. Comparative GEP between BM and MS revealed upregulation of the MAPK/ERK pathway in MS and of gene sets relevant for interaction with the microenvironment. In conclusion, MS is characterized by a high incidence of MAPK/ERK pathway mutations and activation, frequent clonal evolution, and association with CH in elderly patients without recurrent AML-type fusions.
- MeSH
- dioxygenasy genetika MeSH
- dítě MeSH
- DNA vazebné proteiny genetika MeSH
- dospělí MeSH
- GTP-fosfohydrolasy genetika MeSH
- klonální hematopoéza * genetika MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- MAP kinasový signální systém * genetika MeSH
- membránové proteiny genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- myeloidní sarkom * genetika patologie MeSH
- nukleofosmin genetika MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stanovení celkové genové exprese MeSH
- up regulace MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- biopsie metody MeSH
- DNA nádorová analýza MeSH
- karcinom farmakoterapie genetika radioterapie MeSH
- lidé MeSH
- nádory prsu farmakoterapie genetika radioterapie MeSH
- průtoková cytometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
Clonal plants have more traits enabling individual persistence (larger belowground storage of buds and assimilates), whereas non-clonal plants have more traits enabling population persistence (a higher reliance on regeneration from seeds). This difference presumably makes those groups respond differently to disturbance. We asked whether this difference is already expressed in the first year of the plant's life. In a pot experiment with 17 congeneric pairs of clonal and non-clonal herbs, we investigated response to a disturbance at the individual level. We were interested whether the leaf C/N ratio (a proxy reflecting active growth and photosynthetic efficiency), the R/S ratio (a proxy for belowground storage) and the amount of compensated biomass differ between clonal and non-clonal herbs. Moreover, we asked whether compensation for the loss of aboveground biomass after disturbance can be predicted by the R/S ratio or explained by the leaf C/N ratio. We found that clonal herbs have higher leaf C/N and R/S ratios than non-clonal herbs. Under disturbance, the leaf C/N and R/S ratios decreased in the clonal herbs and increased in the non-clonal herbs. However, the clonal and non-clonal plants did not differ in biomass compensation ability. Neither the R/S ratio nor the leaf C/N ratio explained the compensation abilities of the herbs. These results show that even though the growth strategies of clonal and non-clonal plants and their reactions to disturbance are different, the groups are similarly capable of compensating for the loss of aboveground biomass. Clonal plants do not have an advantage over non-clonal plants under disturbance during their first year of life.
- MeSH
- biomasa MeSH
- fotosyntéza MeSH
- listy rostlin * MeSH
- rostliny * MeSH
- Publikační typ
- časopisecké články MeSH
Clonal growth of plants is attained by a number of morphologically different organs (e.g. stolons, rhizomes, and roots), which are not functionally equivalent. Consequently, these clonal growth organ (CGO) types can determine functional traits that are associated with clonality, although little is known about their evolutionary flexibility or the constraining role they play on clonal traits. We investigated the rates of evolutionary change by which individual CGOs are acquired and lost using a set of 2652 species of Central European flora. Furthermore, we asked how these individual CGOs constrain functionally relevant clonal traits, such as lateral spread, number of offspring, and persistence of connections. We show that plants can easily switch in evolution among individual types of CGO and between clonal and nonclonal habits. However, not all these transitions are equally probable. Namely, stem-based clonal growth and root-based clonal growth constitute evolutionarily separate forms of clonal growth. Clonal traits are strongly constrained by individual CGO types. Specifically, fast lateral spread is attained by stolons or hypogeogenous rhizomes, and persistent connections are attained by all rhizome types. However, the ease with which clonal organs appear and disappear in evolution implies that plants can overcome these constraints by adjusting their morphologies.
