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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE46481 | GEO | 2013/12/31

SECONDARY ACCESSION(S): PRJNA200606

REPOSITORIES: GEO

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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

Rescue of murine Gata1s mutant M7 leukemic cells by full-length Gata1

2010-08-01 | GSE16676 | 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

The unique role of GATA1s in Down syndrome acute megakaryocytic leukemia biology and therapy

Project description:Microarray gene expression profiling of lentivirus shRNA knockdown of the GATA1 gene in a DS AMkL cell line, CMK (harbors a mutated GATA1 gene and only expresses GATA1s).

2012-06-01 | GSE32388 | GEO

Rescue of murine Gata1s mutant M7 leukemic cells by full-length Gata1

Project description:In this project, we studied a mouse model of human Down Syndrome (DS) megakaryocytic leukemia involving mutations in the GATA1 transcription factor (called GATA1s mutation). The model was generated through retroviral insertional mutagenesis in Gata1s mutant fetal liver progenitors. In this study, we analyzed the dependency of these leukemic cells on the Gata1s mutant protein. Here we report Gata1s mutant leukemic cells were dependent on this mutant protein. Introduction of the full-length Gata1 protein to these cells led to their reduced proliferation and increased differentiation along the megakaryocytic lineage. We transduced leukemic cells with Gata1/estrogen receptor fusion cDNA (Gata1-ER) and generated stable cell lines. Addition of beta-estradiol to culture medium led to activation of the full-length Gata1 protein in synchronized leukemic cells. Gene expression profiles were collected at multiple time points.

2010-08-01 | E-GEOD-16676 | 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

Murine M7 leukemia derived from retroviral insertional mutagenesis of Gata1s fetal progenitors

Project description:The goal of this study is to derive a mouse model of human Down Syndrome (DS) megakaryocytic leukemia involving mutations in the hematopoietic transcription factor, GATA1 (called GATA1s mutation). We achieved this through transduction of Gata1s mutant fetal progenitors by MSCV-based retrovirus expressing a GFP marker, followed by in vitro selection (for immortalized cell lines), and then in vivo selection (for transformed cell lines) through transplantation. Here we report one such cell line [T6(6)] that gives rise to megakaryocytic leukemia (M7 leukemia) upon transplantation.

2010-08-01 | GSE16682 | GEO

Developmental stage-specific interplay between GATA1 and IGF signaling in fetal hematopoiesis and leukemogenesis

Project description:This SuperSeries is composed of the following subset Series: GSE16676: Rescue of murine Gata1s mutant M7 leukemic cells by full-length Gata1 GSE16677: Gene expression profiling of Down Syndrome (DS)-AMKL and non-DS AMKL samples GSE16679: Plag1 overexpression cooperates with Evi1 overexpression and Gata1s mutation in leading to M7 leukemia GSE16682: Murine M7 leukemia derived from retroviral insertional mutagenesis of Gata1s fetal progenitors GSE16684: Murine M7 leukemia derived from retroviral insertional mutagenesis of Gata1s fetal progenitors depends on IGF signaling Refer to individual Series

2010-08-01 | E-GEOD-16655 | biostudies-arrayexpress

Chromatin occupancy and chromatin status of K562 cells with a mutation causing exclusive expression of N-terminally truncated GATA1 (GATA1s).

Project description:Children with Down syndrome (DS) are at high risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (DS-AMKL). GATA1 gene mutations are detected in almost all TAM and DS-AMKL samples, leading to exclusive expression of short GATA1 protein (GATA1s) lacking of N-terminal domain (NTD). However, it remains to be clarified how GATA1s is involved with both disorders. To investigate how the loss of GATA1 NTD is involved in the molecular mechanisms of leukemogenesis in DS, we established the K562 GATA1s (K562-G1s) clones expressing only GATA1s by CRISPR/Cas9 genome editing. The K562-G1s clones expressed KIT at higher levels compared to the wild type K562 (K562-WT). With Chromatin-Immunoprecipitation (ChIP) studies, we found that both GATA1 and GATA1s were bound upstream of the KIT gene. To understand the status of the KIT gene in K562-WT and one of K562-G1 subclone, C1 #26, we also performed ChIP-seq of histone modifications. Although the ChIP-seq signals of C1 #26 tended to be slightly lower than those of K562-WT, the activation status of the KIT gene demonstrated by the histone modifications was not significantly different between K562-WT and C1#26. Chromosome conformation capture (3C)-modified proximity assays revealed the difference in the conformation of the KIT gene between the K562-WT and C1 #26. We found that the lack of the NTD of GATA1 altered the genomic structure of the KIT gene, resulting in dysregulation of KIT expression. These results suggest that the NTD of GATA1 is essential for proper genomic conformation and gene expression regulation of the KIT gene and that perturbation of this mechanism might be involved in the pathogenesis of TAM and DS-AMKL.

2022-11-29 | GSE159072 | GEO

Murine M7 leukemia derived from retroviral insertional mutagenesis of Gata1s fetal progenitors depends on IGF signaling

2010-08-01 | GSE16684 | GEO

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