Augmented hematopoiesis in induced pluripotent stem cells derived from patients with Down syndrome.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Yasuhiro Ebihara
PROVIDER: E-GEOD-33911 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:To identify the genes, which led to the augmented hematopoiesis in DS-iPS cells, we performed gene expression profiling of D12-DS-iPS cells (DS-iPS-T32, DS-iPS-T33 and DS-iPS-T31) and control hiPS cells (253G1, 253G4 and A31) generated by 3 factors. In the comparison of gene expression levels in each DS-iPS cell clone with the average of these in control iPS cell clones, 972 genes showed more than 2-fold increased expression, and 1118 genes showed decreased expression in all DS-iPS cell clones. Among these upregulated genes, 61 genes including GATA1 were involved in hematopoiesis-related genes according to Ingenuity Pathways Analysis (IPA). Among the above 2-fold more upregulated genes in DS-iPS cells, 18 genes were on Hsa21. The expression of RUNX1 on Hsa21, a hematopoiesis-related gene, was significantly upregulated in DS-iPS cells. The high expressions of GATA1 and RUNX1 were also identified in 4-factor DS-iPS cells.
2011-11-29 | GSE33911 | GEO
Project description:DS children have a 500-fold increased risk for developing acute megakaryoblastic leukemia (AMKL). Around 10% of DS newborns have a transient myeloproliferative disorder (TMD) that resolves spontaneously. Somatic mutations acquired during fetal hematopoiesis in the GATA1 transcription factor are detected in megakaryoblasts from all the DS TMDs or AMKLs. GATA1 is an X chromosome transcription factor essential for the development of multiple hematopoietic lineages. Loss of GATA1 results in embryonic lethality due to severe anemia. The GATA1 mutations result in the expression of a shorter isoform, GATA1s. Replacement of GATA1 with GATA1s causes transient proliferation of immature fetal megakaryocytic progenitors. The Hsa21 ETS transcription factor, ERG, is expressed in megakaryocytes and erythrocytes and is involved in several types of cancer. Mutation in GATA1 gene leading to expression of the short isoform (GATA1s) that occurs on the background of trisomy 21 is regarded as one of the driving forces for megakaryocytic expansion observed in DS fetal livers. ERG, which is located on chromosome 21, is considered one of the leading candidates to cooperate with GATA1 mutation in the generation of DS AMKL. To study the in vivo cooperation between ERG and GATA1 isoforms, we crossed the ERG transgenic mice with the GATA1s Knock-in mice (GATA null background). We found that males expressing both ERG and the short isoform of GATA1(GATA1s) died in uterus between embryonic days E121/2 and E141/2.We studied erythropoiesis and megakaryopoiesis in fetal livers from the different genotypes generated from our cross. We used expression array to study the specific interaction of ERG with the different GATA1 isoforms in fetal livers from E121/2 and E141/2 and identify ERG, GATA1 and GATA1s target genes by comparing sets of genes that are activated or repressed in the presence of ERG and the two isoforms of GATA1.
2013-12-31 | E-GEOD-46481 | biostudies-arrayexpress
Project description:Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that increased DYRK1A expression may be protective against TAM and ML-DS and that DYRK1A inhibition would not be a therapeutic option for GATA1s-associated leukemias.
2023-11-04 | GSE243702 | GEO
Project description:DS children have a 500-fold increased risk for developing acute megakaryoblastic leukemia (AMKL). Around 10% of DS newborns have a transient myeloproliferative disorder (TMD) that resolves spontaneously. Somatic mutations acquired during fetal hematopoiesis in the GATA1 transcription factor are detected in megakaryoblasts from all the DS TMDs or AMKLs. GATA1 is an X chromosome transcription factor essential for the development of multiple hematopoietic lineages. Loss of GATA1 results in embryonic lethality due to severe anemia. The GATA1 mutations result in the expression of a shorter isoform, GATA1s. Replacement of GATA1 with GATA1s causes transient proliferation of immature fetal megakaryocytic progenitors. The Hsa21 ETS transcription factor, ERG, is expressed in megakaryocytes and erythrocytes and is involved in several types of cancer. Mutation in GATA1 gene leading to expression of the short isoform (GATA1s) that occurs on the background of trisomy 21 is regarded as one of the driving forces for megakaryocytic expansion observed in DS fetal livers. ERG, which is located on chromosome 21, is considered one of the leading candidates to cooperate with GATA1 mutation in the generation of DS AMKL. To study the in vivo cooperation between ERG and GATA1 isoforms, we crossed the ERG transgenic mice with the GATA1s Knock-in mice (GATA null background). We found that males expressing both ERG and the short isoform of GATA1(GATA1s) died in uterus between embryonic days E121/2 and E141/2.We studied erythropoiesis and megakaryopoiesis in fetal livers from the different genotypes generated from our cross.
2013-12-31 | GSE46481 | GEO
Project description:Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS fetal livers precedes the acquisition of GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes due trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Correlation of gene expression changes caused by Erg trisomy in Ts(1716)65Dn multilineage progenitor cells with those associated with trisomy 21 in human DS HSCs support a role for ERG as a regulator of hematopoietic lineage potential, trisomy of which drives pre-leukemic changes in DS fetal livers that predispose to subsequent DS-TMD and DS-AMKL.
2015-04-15 | E-MTAB-2574 | biostudies-arrayexpress
Project description:Down syndrome (DS) is caused by triplication of Human chromosome 21 (Hsa21) and associated with an array of deleterious phenotypes, including mental retardation, heart defects and immunodeficiency. Spatio-temporal patterns of genome-wide expression are critical to the understanding of DS. We used a Human Exon microarray to characterize gene expression in peripheral blood cells derived from DS and control individuals from two age groups: neonate (N) and child (C). A total of 174 transcript clusters (gene-level) with eight located on Hsa21 in N group and 383 transcript clusters including 57 on Hsa21 in C group were significantly dysregulated in DS individuals. Except for 22 commonly dysregulated genes in the two groups, the remaining dysregulated genes were different between N and C groups, reflecting temporally dynamic variation in gene expression in DS. Dramatically fewer dysregulated Hsa21 genes in N group than those in C group suggested that triplication of Hsa21 per se induces a moderate deregulation at early developmental stages. Further functional analysis revealed that the dysregulated genes in DS were significantly enriched in two KEGG pathways in N group and six pathways in C group. These pathways included leukocyte trans-endothelial migration, B cell receptor signaling pathway and primary immunodeficiency, etc., which causally implicated dysfunctional immunity in DS. Our results provided a comprehensive picture of expression patterns of DS at the two developmental stages and point towards candidate genes and molecular pathways potentially associated with the immune dysfunction in DS. All 37 samples, including 15 DS patients and 22 control individuals were analysized and divided into two age-matched groups: N group (5 DS versus 7 control individuals, age: 3 days to 38 days) and C group (10 DS versus 15 control individuals, age: 1 year to 13 years). N group includes DS (D11-D15) and Control (C16-C22), and C group includes DS (D1-D10) and Control (C1-C15).
2012-02-10 | E-GEOD-35665 | biostudies-arrayexpress
Project description:Down syndrome (DS) is caused by triplication of Human chromosome 21 (Hsa21) and associated with an array of deleterious phenotypes, including mental retardation, heart defects and immunodeficiency. Genome-wide expression patterns of uncultured peripheral blood cells are useful to understanding of DS-associated immune dysfunction. We used a Human Exon microarray to characterize gene expression in uncultured peripheral blood cells derived from DS individuals and age-matched controls from two age groups: neonate (N) and child (C). A total of 174 transcript clusters (gene-level) with eight located on Hsa21 in N group and 383 transcript clusters including 56 on Hsa21 in C group were significantly dysregulated in DS individuals. Microarray data were validated by quantitative polymerase chain reaction. Functional analysis revealed that the dysregulated genes in DS were significantly enriched in two and six KEGG pathways in N and C group, respectively. These pathways included leukocyte trans-endothelial migration, B cell receptor signaling pathway and primary immunodeficiency, etc., which causally implicated dysfunctional immunity in DS. Our results provided a comprehensive picture of gene expression patterns in DS at the two developmental stages and pointed towards candidate genes and molecular pathways potentially associated with the immune dysfunction in DS.
2012-02-10 | GSE35665 | GEO
Project description:Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
2016-06-17 | GSE83449 | GEO
Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
2023-05-10 | PXD030616 | Pride
Project description:Down syndrome (DS) results from trisomy of human chromosome 21 (HSA21), and DS research has been greatly advanced by the use of mouse models. We previously generated a humanized mouse model of DS, TcMAC21, which carries the long arm of HSA21. These mice exhibit learning and memory deficits, and may reproduce neurodevelopmental alterations observed in humans with DS. Here we performed histologic studies of the TcMAC21 forebrain from embryonic to adult stages. The TcMAC21 neocortex showed reduced proliferation of neural progenitors and delayed neurogenesis. These abnormalities were associated with a smaller number of projection neurons and interneurons. Further, (phospho-)proteomic analysis of adult TcMAC21 cortex revealed alterations in the phosphorylation levels of a series of synaptic proteins. The TcMAC21 mouse model shows similar brain development abnormalities as DS, and will be a valuable mode to investigate prenatal and postnatal causes of intellectual disability in humans with DS.
2023-10-23 | PXD044343 | Pride