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Augmented hematopoiesis in induced pluripotent stem cells derived from patients with Down syndrome.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33911 | GEO | 2011/11/29

SECONDARY ACCESSION(S): PRJNA148247

REPOSITORIES: GEO

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Augmented hematopoiesis in induced pluripotent stem cells derived from patients with Down syndrome.

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. Gene expression in blood cells differentiated from human induced pluripotent stem cells derived from patients with Down syndrome and healthy donor was measured in 12 days after induction of differentiation. Eight cell lines were used.

2011-11-29 | E-GEOD-33911 | biostudies-arrayexpress

RUNX1 isoforms in leukemogenesis

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

Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis

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

Expression data from transgenic ERG, GATA1s KI and ERG/GATA1s fetal livers

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

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis

Project description:Background: Down syndrome (DS) is associated with a wide range of phenotypes. To address the hypothesis that the genome-wide perturbation of gene regulation in DS is modulated by epigenetic changes, we performed an epigenome-wide association study (EWAS) on neonatal bloodspots comparing 196 newborns with DS and 439 newborns without DS. Results: We identified 652 epigenome-wide significant CpGs (P<7.67x10-8) and 1,052 differentially methylated regions (DMRs) across the genome. Differential methylation at promoters/enhancers correlated with gene expression changes in DS versus non-DS fetal liver hematopoietic stem/progenitor cells (HSPC) (P<0.0001). Two of the top 3 DS-associated CpGs overlapped RUNX1, and were highly significantly hypermethylated in DS newborns (P<1.0x10-21). The top two DMRs overlapped promoters of RUNX1 and FLI1, both important regulators of megakaryopoiesis. FLI1 expression was markedly reduced in DS fetal liver HSCs (P<0.0001) and myeloid progenitors (P<0.0001). By contrast, RUNX1 expression was increased in DS fetal liver myeloid progenitors (P<0.0001), consistent with selective hypermethylation of the RUNX1 P2 promoter, which dominates in embryonic development, but sparing the P1 promoter that drives definitive hematopoiesis. Targeted sequencing of GATA1 revealed somatic, preleukemic mutations in 16.3% DS newborns, consistent with the high frequency of these mutations in DS newborns. Removal of DS newborns with GATA1 mutations had minimal impact on the EWAS results. Conclusions: DS has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with DS. Blood-detectable DS-related epigenetic changes may underlie an array of DS outcomes, including neurologic and immune-related morbidities.

2020-12-04 | GSE160637 | GEO

Expression data from transgenic ERG, GATA1s KI and ERG/GATA1s fetal livers

2013-12-31 | GSE46481 | GEO

A mouse Embryonic Stem Cell Bank for inducible overexpression of human chromosome 21 genes

2010-12-06 | GSE19836 | GEO

A mouse Embryonic Stem Cell Bank for inducible overexpression of human chromosome 21 genes

Project description:The HSA21-mES Cell Bank includes, in triplicate clones, thirty-two murine orthologs of HSA21 genes, which can be overexpressed in an inducible manner using the Tet-off system integrated in the Rosa26 locus. The following subset of twenty clones were characterized by microarray analysis: Bach1, Erg, Ets2, Gabpa, ZFP295, Nrip1, Olig1, Olig2, Pknox1, 1810007M14Rik, Runx1, Aire, Sim2, Dscr1, DYRK1A, SNF1LK, Ripk4 , Hunk, Pdxk, Pfkl. Each triplicate clone was transcriptionally profiled by microarray analysis using Affymetrix Mouse 430_2 arrays before and after induction (Affymetrix 430A_2 in case of Runx1), yielding six arrays for each overexpression experiment.

2010-12-06 | E-GEOD-19836 | biostudies-arrayexpress

caArray_orkin-0038: Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

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

Transcription profiling by array of the Ts(1716)65Dn Down syndrome mouse model bone marrow lineage- c-Kit+ Sca-1+ (LSK), CMP, GMP and MEP progenitor cell populations, in which trisomy of Erg was specifically reduced to disomy using the Mld2 allele

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

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