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Murine ML-DS-like leukemias

ABSTRACT: Modelling the progression from TAM to ML-DS in children with Down syndrome utilizing a murine transplantation model

PROVIDER: PRJEB30376 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3001940.fastq.gz	Fastqsanger.gz
	ERR3001950.fastq.gz	Fastqsanger.gz
	ERR3001960.fastq.gz	Fastqsanger.gz
	ERR3001970_1.fastq.gz	Fastqsanger.gz
	ERR3001970_2.fastq.gz	Fastqsanger.gz

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RNA sequencing data from Myeloid Leukaemia of Down Syndrome (ML-DS)

Project description:RNA sequencing data from Myeloid Leukaemia of Down Syndrome (ML-DS)

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Multiplexed DNA high throughput genotyping study to determine the mutational status of transient (TAM) and acute myeloid leukaemic (ML-DS) Down syndrome individuals.

Project description:We used a 48.48 Fluidigm Access Array approach (1070 Amplicons spanning 62 genes: 157kB coverage) of genomic DNA from over 100 samples to genotype individuals with transient abnormal myelopoiesis (TAM) and acute myeloid leukemia of Down syndrome (ML-DS). Individually barcoded patient samples were subjected to paired-end 150bp sequencing (Illumina MiSeq), including paired GATA1 variant negative controls (including Post treatment) and 8 known reference GATA1- controls. Samples were mapped to build 37 of the human reference genome and subject to bioinformatic analysis (Varscan, Pindel, GATK) to facilitate the characterisation of known gene mutations in cancer as well as the identification / validation of potentially novel variants.

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Affymetrix SNP array data for xenografted transient abnormal myelopoiesis samples

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RNA sequencing data from Myeloid Leukaemia of Down Syndrome (ML-DS)

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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

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Multiplexed DNA high throughput genotyping study to determine the mutational status of transient (TAM) and acute myeloid leukaemic (ML-DS) Down syndrome individuals.

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Affymetrix SNP array data for xenografted transient abnormal myelopoiesis samples

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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.

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INCLUDE: Mechanisms, Genomic Risk Stratification and Precision Intervention for Acute Myeloid Leukemia in Children with Down syndrome (ML-DS)

Project description:INCLUDE: Mechanisms, Genomic Risk Stratification and Precision Intervention for Acute Myeloid Leukemia in Children with Down syndrome (ML-DS)

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