Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome.
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ABSTRACT:
SUBMITTER: Yamato G
PROVIDER: S-EPMC8102190 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6824893 | biostudies-literature
Project description:BackgroundDown syndrome myeloid hyperplasia includes transient abnormal myelopoiesis (TAM) and the myeloid leukemia associated with Down syndrome (ML-DS). The mutation of GATA1 gene is essential in the development of Down syndrome combined with TAM or ML-DS. Some patients with TAM are asymptomatic and may also present with severe manifestations such as hepatosplenomegaly and hydrops.Case presentationWe report two cases of prenatally diagnosed TAM. One case was a rare placental low percentage 21 trisomy mosiacism, resulting in the occurrence of a false negative NIPT. The final diagnosis was made at 36 weeks of gestation when ultrasound revealed significant enlargement of the foetal liver and spleen and an enlarged heart; the foetus eventually died in utero. We detected a placenta with a low percentage (5-8%) of trisomy 21 mosiacism by Copy Number Variation Sequencing (CNV-seq) and Fluorescence in situ hybridization (FISH). In another case, foetal oedema was detected by ultrasound at 31 weeks of gestation. Two foetuses were diagnosed with Down syndrome by chromosomal microarray analysis via umbilical vein puncture and had significantly elevated cord blood leucocyte counts with large numbers of blasts. The GATA1 Sanger sequencing results suggested the presence of a [NM_002049.4(GATA1):c.220G > A (p. Val74Ile)] hemizygous variant and a [NM_002049.4(GATA1):c.49dupC(p. Gln17ProfsTer23)] hemizygous variant of the GATA1 gene in two cases.ConclusionIt seems highly likely that these two identified mutations are the genetic cause of prenatal TAM in foetuses with Down syndrome.
| S-EPMC10588144 | biostudies-literature
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
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
Project description:Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34(+)-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. Although GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1(?e2) knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.
| S-EPMC4047213 | biostudies-literature
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
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
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.
2013-03-01 | GSE44739 | GEO
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
Project description:Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we analyzed the effect of on gene expression upon ectopic expression of Gata1s or Gata1, while simultaneously knocking down endogenous GATA1, in wild-type CD34+-hematopoietic stem and progenitor cells during myeloid differentiation. Ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network.
2014-03-28 | GSE56332 | GEO