ETS2, ERG promote megakaryopoiesis, synergize with alterations in GATA1 to immortalize hematopoietic progenitor cells
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PROVIDER: PRJNA111647 | ENA |
REPOSITORIES: ENA
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Project description:Serial replated GFP + lineage negative cells from Gata1deltaneodeltaHS fetal liver hematopoietic progenitors for 4 generations in methocult M3234 under megakaryocyte promoting conditions, IL3, TPO, IL6, and IL11. Cells were subject to retro-viral infection with MIGR1GFP, MIGR1ETS2, MIGR1ERG, and MIGR1FLI1. Comparison of gene expression profile for GFP + immortalized MIGR1-GFP Gata1deltaneodeltaHS fetal liver progenitors to that of GFP+ Gata1deltaneodeltaHS MIGR1-ETS2, MIGR1-ERG, and MIGR1FLI1 fetal liver progenitors
2010-06-23 | E-GEOD-14506 | biostudies-arrayexpress
Project description:Serial replated GFP + lineage negative cells from Gata1deltaneodeltaHS fetal liver hematopoietic progenitors for 4 generations in methocult M3234 under megakaryocyte promoting conditions, IL3, TPO, IL6, and IL11. Cells were subject to retro-viral infection with MIGR1GFP, MIGR1ETS2, MIGR1ERG, and MIGR1FLI1.
2009-02-16 | GSE14506 | 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:ETS2 and ERG are transcription factors, encoded on human chromosome 21 (Hsa21), that have been implicated in human cancer. People with Down syndrome (DS), who are trisomic for Hsa21, are predisposed to acute megakaryoblastic leukemia (AMKL). DS-AMKL blasts harbor a mutation in GATA1, which leads to loss of full-length protein but expression of the GATA-1s isoform. To assess the consequences of ETS protein misexpression on megakaryopoiesis, we expressed ETS2, ERG, and the related protein FLI-1 in wild-type and Gata1 mutant murine fetal liver progenitors. These studies revealed that ETS2, ERG, and FLI-1 facilitated the expansion of megakaryocytes from wild-type, Gata1-knockdown, and Gata1s knockin progenitors, but none of the genes could overcome the differentiation block characteristic of the Gata1-knockdown megakaryocytes. Although overexpression of ETS proteins increased the proportion of CD41(+) cells generated from Gata1s-knockin progenitors, their expression led to a significant reduction in the more mature CD42 fraction. Serial replating assays revealed that overexpression of ERG or FLI-1 immortalized Gata1-knockdown and Gata1s knockin, but not wild-type, fetal liver progenitors. Immortalization was accompanied by activation of the JAK/STAT pathway, commonly seen in megakaryocytic malignancies. These findings provide evidence for synergy between alterations in GATA-1 and overexpression of ETS proteins in aberrant megakaryopoiesis.
| S-EPMC2665899 | biostudies-literature
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:Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis
| PRJNA1019660 | ENA
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:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors. Genome-wide chromatin occupancy using ChIP-seq on 4 transcription factors (GATA1, GATA2, TAL1, and FLII) and three histone marks (H3K4me1, H3K4me3, and H3K27me3) in lineage-commited primary erythoblasts (ERY) and primary cultured megakaryocytes (MEG).
2014-11-14 | E-GEOD-51337 | biostudies-arrayexpress
Project description:TMPRSS2-ERG gene fusions that are frequently identified in prostate cancer can be generated either through chromosomal translocation or via interstitial deletion. The latter mechanism deletes an interstitial region of ~3Mb and it remains largely unanswered whether genes deleted within this region contribute to prostate cancer. By characterizing two knockin mouse models recapitulating TMPRSS2-ERG fusions with or without the interstitial deletion, we found that only those with deletion developed poorly differentiated adenocarcinomas with epithelial-to-mesenchymal transition, when under a Pten-null background. We identified several interstitial genes, including ETS2 and BACE2, whose reduced expression correlates with worse disease-free survival and lethal disease. By using an Ets2 conditional knockout allele, we demonstrated that loss of one copy of Ets2 was sufficient for prostate cancer progression when under a Pten-null background. Collectively, our data suggest that ETS2 is a prostate tumor suppressor and haploinsufficiency of one or more interstitial genes contributes to prostate cancer progression.
2015-12-31 | GSE63070 | GEO
Project description:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, SCL/TAL1 and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, SCL/TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-specific cis-regulatory modules in multipotential hematopoietic progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming occurs is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential precursor via overlapping and divergent functions of shared hematopoietic transcription factors. Gene expression changes during the development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells
2013-08-09 | E-GEOD-49664 | biostudies-arrayexpress