Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Two Novel GATA1 Mutations in Transient Abnormal Myelopoiesis of Thai Neonates with Down Syndrome.

ABSTRACT: Children with Down syndrome (DS) are 150 times more likely to develop acute myeloid leukemia (ML-DS), compared with those without. One risk factor is transient abnormal myelopoiesis (TAM). Somatic truncating GATA1 mutations are found in most TAM patients and are markers for future ML-DS. We identified two novel frameshift mutations in our seven newborns with DS and TAM: a heterozygous mutation of 17 nucleotide duplication (c.154_170 dup) and a heterozygous 9-nucleotide deletion combined with a 2-nucleotide insertion (c.150_158delins CT). Both mutations introduced a truncated GATA1 protein. Thus, neonates with DS and TAM require frequent ML-DS monitoring.

SUBMITTER: Chukua K

PROVIDER: S-EPMC6824893 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Two Novel <i>GATA1</i> Mutations in Transient Abnormal Myelopoiesis of Thai Neonates with Down Syndrome.

Chukua Kanokporn K Netsawang Chayanont C Padungthai Kittipoom K Khetkham Thanitchet T Chokevittaya Piyaporn P Poonjearansilp Onapinya O Prachuktum Sariya S Kositamongkol Sudatip S Techasatit Wiliporn W Silapamongkolkul Phakatip P Satayasai Wallee W Pusongchai Tasama T Surapolchai Pacharapan P Rojnueangnit Kitiwan K

Journal of pediatric genetics 20190911 4

Children with Down syndrome (DS) are 150 times more likely to develop acute myeloid leukemia (ML-DS), compared with those without. One risk factor is transient abnormal myelopoiesis (TAM). Somatic truncating <i>GATA1</i> mutations are found in most TAM patients and are markers for future ML-DS. We identified two novel frameshift mutations in our seven newborns with DS and TAM: a heterozygous mutation of 17 nucleotide duplication (c.154_170 dup) and a heterozygous 9-nucleotide deletion combined w ...[more]

PMID: 31687255

Similar Datasets

Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome.

Project description: Not available

| S-EPMC8102190 | biostudies-literature

Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia.

Project description: Not available

| S-EPMC8324475 | biostudies-literature

Treatment and prognostic impact of transient leukemia in neonates with Down syndrome.

Project description:Approximately 10% of the neonates with Down syndrome (DS) exhibit a unique transient leukemia (TL). Though TL resolves spontaneously in most patients, early death and development of myeloid leukemia (ML-DS) may occur. Prognostic factors as well as treatment indication are currently uncertain. To resolve that issue, we prospectively collected clinical, biologic, and treatment data of 146 patients with TL. The 5-year overall survival (OS) and event-free survival (EFS) were 85% plus or minus 3% and 63% plus or minus 4%, respectively. Multivariate analysis revealed a correlation between high white blood cell (WBC) count, ascites, preterm delivery, bleeding diatheses, failure of spontaneous remission, and the occurrence of early death. Treatment with cytarabine (0.5-1.5 mg/kg) was administered to 28 patients with high WBC count, thrombocytopenia, or liver dysfunction. The therapy had a beneficial effect on the outcome of those children with risk factors for early death (5-year EFS, 52% +/- 12% vs 28% +/- 11% [no treatment]; P = .02). Multivariate analysis demonstrated its favorable prognostic impact. A total of 29 (23%) patients with TL subsequently developed ML-DS. Patients with ML-DS with a history of TL had a significantly better 5-year EFS (91% +/- 5%) than those without documented TL (70% +/- 4%), primarily due to a lower relapse rate. A history of TL may therefore define a lower-risk ML-DS subgroup. This study was registered at www.clinicaltrials.gov as no. NCT 00111345.

| S-EPMC2265448 | biostudies-literature

Affymetrix SNP array data for xenografted transient abnormal myelopoiesis samples

Project description:Transient abnormal myelopoiesis (TAM) is a clonal pre-leukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, IL-2Rγnull mice. In serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from murine bone marrow (hCD45 sorted) or human peripheral blood samples. Copy number analysis of Affymetrix 500K SNP arrays was performed for xenografted TAM samples of 3 patients. There are also 3 samples from TAM patients in remission, which were used as references for copy number inference.

2013-03-01 | E-GEOD-44739 | biostudies-arrayexpress

Bacterial contig map of the 21q11 region associated with Alzheimer's disease and abnormal myelopoiesis in Down syndrome.

Project description:We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in human chromosome 21q11-q21, encompassing the region of elevated disomic homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as well as the markers, which has shown a strong association with Alzheimer's Disease that has never been explained. The map contains 89 overlapping PACs, BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of 140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by cDNA selection, exon trapping, and/or global EST sequencing have been positioned onto the map, and the only two genes so far mapped to this cytogenetic region, STCH and RIP140 have been precisely localized. This work converts a further 10% of chromosome 21q into a high-resolution bacterial contig map, which will be the physical basis for the long-range sequencing of this region. The map will also enable positional derivation of new transcribed sequences, as well as new polymorphic probes, that will help in elucidation of the role the genes in this region may play in abnormal myelopoiesis and leukemia associated with trisomy 21 and Alzheimer's Disease.

| S-EPMC310710 | biostudies-literature

GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder.

Project description:IntroductionChildren with Down syndrome (DS) are at increased risk of developing distinctive clonal myeloid disorders, including transient abnormal myelopoiesis (TAM) and myeloid leukaemia of DS (ML-DS). TAM connotes a spontaneously resolving congenital myeloproliferative state observed in 10%-20% of DS newborns. Following varying intervals of apparent remission, a proportion of children with TAM progress to develop ML-DS in early childhood. Therefore, TAM and ML-DS represent a biological continuum. Both disorders are characterised by recurring truncating somatic mutations of the GATA1 gene, which are considered key pathogenetic events.MethodsWe herein report, to our knowledge, the first observation on the frequency and nature of GATA1 gene mutations in a cohort of Malaysian children with DS-associated TAM (n = 9) and ML-DS (n = 24) encountered successively over a period of five years at a national referral centre.ResultsOf the 29 patients who underwent GATA1 analysis, GATA1 mutations were observed in 15 (51.7%) patients, including 6 (75.0%) out of 8 patients with TAM, and 9 (42.9%) of 21 patients with ML-DS. All identified mutations were located in exon 2 and the majority were sequence-terminating insertions or deletions (66.7%), including several hitherto unreported mutations (12 out of 15).ConclusionThe low frequency of GATA1 mutations in ML-DS patients is unusual and potentially indicates distinctive genomic events in our patient cohort.

| S-EPMC4971451 | biostudies-literature

Affymetrix SNP array data for xenografted transient abnormal myelopoiesis samples

2013-03-01 | GSE44739 | GEO

Modeling Transient Abnormal Myelopoiesis Using Induced Pluripotent Stem Cells and CRISPR/Cas9 Technology.

Project description:Approximately 1%-2% of children with Down syndrome (DS) develop acute myeloid leukemia (AML) prior to age 5 years. AML in DS children (ML-DS) is characterized by the pathognomonic mutation in the gene encoding the essential hematopoietic transcription factor GATA1, resulting in N-terminally truncated short form of GATA1 (GATA1s). Trisomy 21 and GATA1s together are sufficient to induce transient abnormal myelopoiesis (TAM) exhibiting pre-leukemic characteristics. Approximately 30% of these cases progress into ML-DS by acquisition of additional somatic mutations. We employed disease modeling in vitro by the use of customizable induced pluripotent stem cells (iPSCs) to generate a TAM model. Isogenic iPSC lines derived from the fibroblasts of DS individuals with trisomy 21 and with disomy 21 were used. The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 system was used to introduce GATA1 mutation in disomic and trisomic iPSC lines. The hematopoietic stem and progenitor cells (HSPCs) derived from GATA1 mutant iPSC lines expressed GATA1s. The expression of GATA1s concomitant with loss of full-length GATA1 reduced the erythroid population, whereas it augmented megakaryoid and myeloid populations, characteristic of TAM. In conclusion, we have developed a model system representing TAM, which can be used for modeling ML-DS by stepwise introduction of additional mutations.

| S-EPMC7558799 | biostudies-literature

Cytokine profiling in 128 patients with transient abnormal myelopoiesis: a report from the JPLSG TAM-10 trial.

Project description:AbstractTransient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418.

| S-EPMC11222942 | biostudies-literature

Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971.

Project description:Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.

| S-EPMC3245202 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data