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Gene expression profiling of Down Syndrome (DS)-AMKL and non-DS AMKL samples

ABSTRACT: The goal of this study is to define a gene expression signature unique to DS-AMKL (acute megakaryoblastic leukemia or FAB M7 leukemia). A similar study was done previously, but using unfractionated patient leukemic samples. In this study, we sorted megakaryocytic leukemia blasts from patients and then compared their gene expression signatures to those from similarly sorted blasts from patients with non-DS AMKL. This allowed us to identify a gene expression signature more unique to DS-AMKL samples. The leukemic blasts were sorted based on CD41, CD7, CD117, CD33, and CD34 antibodies as previously described (Klin. Padiatr. 217, 126-134).

ORGANISM(S): Homo sapiens

SUBMITTER: Zhe Li

PROVIDER: E-GEOD-16677 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis.

Klusmann Jan-Henning JH Godinho Frank J FJ Heitmann Kirsten K Maroz Aliaksandra A Koch Mia Lee ML Reinhardt Dirk D Orkin Stuart H SH Li Zhe Z

Genes & development 20100801 15

Oncogene-mediated transformation of hematopoietic cells has been studied extensively, but little is known about the molecular basis for restriction of oncogenes to certain target cells and differential cellular context-specific requirements for oncogenic transformation between infant and adult leukemias. Understanding cell type-specific interplay of signaling pathways and oncogenes is essential for developing targeted cancer therapies. Here, we address the vexing issue of how developmental restr ...[more]

PMID: 20679399

Similar Datasets

Gene expression profiling of Down Syndrome (DS)-AMKL and non-DS AMKL samples

Project description:The goal of this study is to define a gene expression signature unique to DS-AMKL (acute megakaryoblastic leukemia or FAB M7 leukemia). A similar study was done previously, but using unfractionated patient leukemic samples. In this study, we sorted megakaryocytic leukemia blasts from patients and then compared their gene expression signatures to those from similarly sorted blasts from patients with non-DS AMKL. This allowed us to identify a gene expression signature more unique to DS-AMKL samples.

2010-08-01 | GSE16677 | 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

Expression data of human mesenchymal stromal cells isolated from bone marrow of ML-DS, AMKL patients and HD

Project description:Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and here especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSCs) and cytokines specifically released by the myeloid blasts are the main drivers of fibrosis in the bone marrow niche (BMN). In order to determine which factors are necessary/sufficient for the BMF, we first established MSCs from pediatric patients with AMKL and ML-DS. Healthy donor (HD) control MSCs were established from children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential, enrichment of proliferation-associated genes and upregulation of the oncofetal protein IF2B3. TGFB1 exposure in vitro promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an in vivo humanized artificial BMN in immunodeficient mice. Injection of AMKL blasts as producers of TGFB1 specifically induced fibrosis grade I/II in a dose-dependent fashion, thus strongly suggesting TGFB1 excess to be sufficient for BMF. Our in vivo BMF model will be instrumental to specifically prevent the BMF and to identify potentially druggable target genes. We used microarrays to obtain a global overview of the differences between undifferentiated ML-DS- and AMKL-MSC compared to HD-MSC

2020-07-27 | GSE138861 | 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. Since the leukemic cells were retrovirally tagged with a GFP reporter, we sorted GFP+ leukemic blasts and generated their expression profiles by microarray.

2010-08-01 | E-GEOD-16682 | biostudies-arrayexpress

Role of trisomy 21, GATAs mutation and associated mutations in the development of a DS-AMKL model from IPSC: Cut&Tag

Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modelled this leukemic evolution through stepwise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. Cut&Tag against GATA1 was performed on CD41+CD42+ megakaryocytes obtained after 18 days of differentiation of the IPSC clones. 500,000 CD41+CD42+ MK sorted cells were used to analyze GATA1 and GATA1s chromatin occupancy using the CUT&Tag-IT Assay Kit (Active Motif) according to the manufacturer recommendations. Briefly, cells were bound to Concanavalin A-Coated Beads and incubated with primary anti-GATA1 antibody in buffer with Protease Inhibitor Cocktail and 5% digitonine overnight at 4°C under rotation. The Guinea Pig anti-rabbit secondary antibody was incubated in Dig-Wash buffer for 1 hour at RT under rotation. After 3 washes, the CUT&Tag-IT™ Assembled pA-Tn5 Transposomes (1:100) were added for 1 hour at RT under rotation and tagmentation was performed during 1 hour at 37°C. DNA was purified and libraries were generated by PCR. The final libraries were purified, pooled together in equal concentrations and subjected to paired-end sequencing (100 cycles: 2x50) in Novaseq-6000 sequencer (Illumina) at Gustave Roussy.

2022-09-30 | E-MTAB-11032 | biostudies-arrayexpress

Role of trisomy 21, GATAs mutation and associated mutations in the development of a DS-AMKL model from IPSC: RNAseq

Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled this leukemic evolution through step-wise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. For RNAseq, each condition was represented by a randomly selected clone and all the clones were isogenically compared. Cells were labeled with APC, BV421 and PE-conjugated antibodies against CD41a, CD42b and CD33 (see Table S5), respectively. In order to obtain a highly purified megakaryocytes, CD33+ cells were removed from the double positive CD41, CD42 population during cell sorting. After sorting, the purity was verified and corresponded to 98-100% of CD41+, CD42+, CD33. Total RNA was extracted using RNA/DNA/Protein Purification Plus Kit (Proteigene, St Marcel, France). Whole transcriptome sequencing was performed at the GenomEast Platform (Illkirch, France). cDNA libraries were synthesized from 250 ng total RNA using TruSeq Strandard mRNA Kit (Illumina). Libraries were verified for their amount and quality by capillary electrophoresis using a 2100 Bioanalyzer (Agilent Technologies). Sequencing was performed at 2100 bp using the Illumina HiSeq 4000 technology, yielding > 40 million reads per sample.

2022-09-29 | E-MTAB-11033 | biostudies-arrayexpress

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

Role of trisomy 21, GATAs mutation and associated mutations in the development of a DS-AMKL model from IPSC: Single cell RNAseq

Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modelled this leukemic evolution through stepwise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. Single cell analysis was performed on hematopoietic cells obtained from IPSC clones after 13 days of differentiation. Sample preparation was done at room temperature. Single-cell suspensions were loaded onto a Chromium Single Cell Chip (10x Genomics) according to the manufacturer’s instructions for co-encapsulation with barcoded Gel Beads at a target capture rate of ~10,000 individual cells per sample. Captured mRNAs were barcoded during cDNA synthesis using the Chromium Next GEM Single Cell 3' GEM, Library & Gel Bead Kit v3.1 (10X Genomics) according to the manufacturer’s instructions. All samples were processed simultaneously with the Chromium Controller (10X Genomics) and the resulting libraries were prepared in parallel in a single batch. We pooled all of the libraries for sequencing in a single SP Illumina flow cell. All of the libraries were sequenced with an 8-base index read, a 28-base Read1 containing cell-identifying barcodes and unique molecular identifiers (UMIs), and a 91-base Read2 containing transcript sequences on an Illumina NovaSeq 6000.

2022-09-29 | E-MTAB-11036 | biostudies-arrayexpress

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

Identification differentially expressed genes upon valproic acid treatment

Project description:The goal of this study is to define genes that are differentially expressed in Down syndrome leukemic blasts after treatment with valproic acid (VPA) Here we report the identification gene sets that are downregulated in Down syndrome leukemic cell lines after exposure to valproic acid (VPA) CMK and CMY cells were treated with VPA for 24h and 48h with 1mM or 2mM VPA. Their gene expression profile was compared against the untreated control.

2011-07-12 | E-GEOD-30517 | biostudies-arrayexpress

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