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Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs [Bisulfite-Seq]

ABSTRACT: Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs [Bisulfite-Seq]

PROVIDER: PRJNA1148926 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30273206.fastq.gz	Fastqsanger.gz
	SRR30273207.fastq.gz	Fastqsanger.gz
	SRR30273208.fastq.gz	Fastqsanger.gz
	SRR30273209.fastq.gz	Fastqsanger.gz
	SRR30273210.fastq.gz	Fastqsanger.gz

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Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs [Bisulfite-Seq]

Project description:Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.

2025-04-01 | GSE274997 | GEO

Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs [RNA-Seq]

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Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs

Project description:Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs

| PRJNA1148925 | ENA

Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs [RNA-Seq]

Project description:Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs [RNA-Seq]

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The impact of decitabine treatment in MDS-induced Tet2KD/KDEzh2Δ/Δ LSK HSPCs

Project description:To evaluate the impact of DNA demethylating agents on our mouse MDS model, we chose 5-aza-2’-deoxycytidine, decitabine (DAC), one of the DNA demethylating agents, which is incorporated into DNA but not RNA and has 10-fold more potency in DNA demethylation than 5-azacitidine. We transplanted Tet2KD/KDEzh2Δ/Δ MDS cells into lethally irradiated secondary recipients and treated them with DAC (low dose DAC at 0.25mg/kg, 3 times a week, intraperitoneal injection), then purified LSK HSPCs and evaluated the expression profiles.

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RNA-seq of healthy CD34+ HSPCs after co-culture with myelodyplastic syndrome patient-derived mesenchymal stromal cells

Project description:Cytopenia in at least one of the hematopoietic lineages (RBCs, WBCs or platelets) is a hallmark feature of MDS, indicating the lack of ability to support HSPC proliferation and the retention of their multilineage potential in the bone marrow. Here, wel investigate MDS-MSCs (with and without 5-azacitidine pre-treatment) as feeder layers for healthy CD34+ HSPCs. We performed RNA sequencing of co-cultured CD34+ HSPCs to compare their transcriptomic signatures after exposure to treated vs untreated MDS-MSCs.

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Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs

Project description:SF3B1 K700E is the most frequent mutation in myelodysplastic syndrome (MDS), but the mechanisms by which it drives MDS pathogenesis remain unclear. We derived a panel of 18 genetically matched SF3B1 K700E- and SF3B1 WT-induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1 K700E mutations and performed RNA and ATAC sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from them. We developed a novel computational framework integrating splicing with transcript usage and gene expression analyses and derived a SF3B1 K700E splicing signature consisting of 59 splicing events linked to 34 genes, which associates with the SF3B1 mutational status of primary MDS patient cells. The chromatin landscape of SF3B1 K700E HSPCs showed increased priming toward the megakaryocyte- erythroid lineage. Transcription factor motifs enriched in chromatin regions more accessible in SF3B1 K700E cells included, unexpectedly, motifs of the TEAD family. TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1 K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1 K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.

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Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-04-01 | GSE275000 | GEO

Epigenome analysis of normal and myelodysplastic sundrome (MDS) bone marrow derived mesenchymal stromal cells (MSCs)

Project description:Methylation data for MDS bone marrow derived MSCs before and after 5-Azacitidine treatment. Methylation profiles were measured using the Infinium Human MethylationEPIC BeadChip (Illumina). There are 5 healthy MSC and 8 high-risk MDS-MSC samples, untreated and treated with 5-Azacitidine in vitro.

2019-09-06 | GSE119617 | GEO

TET2 deficiency promotes MDS-associated leukemogenesis

Project description:Loss of function TET2 mutations are frequently seen in myelodysplastic syndrome (MDS) patients. Previous studies have demonstrated that TET2 deficiency enhances maintenance of MDS hematopoietic stem and progenitor cells (HSPCs). Nonetheless, the pathogenic role of TET2 in MDS progression remains elusive. Here, we demonstrate Tet2 knockout (KO) markedly accelerated malignant transformation in Nup98-HoxD13 (NHD13) transgenic mice and promotes leukemogenesis of HoxA9 transduction/transplant mice. Consistently, low TET2 level cooperating with high HOXA9 level predicts poor outcome of MDS patients. Notably, Tet2 KO conferred a clonal advantage to the HSPCs of NHD13 mice. Whole-exome sequencing revealed that Tet2 KO facilitates accumulation of mutations at genes associated with leukemogenesis, including Arih2, whose loss of function promotes MDS cells proliferation. Using 5-hydroxymethylcytosine immunoprecipitation coupled with high-throughput sequencing analysis, we found while Tet2 deletion decreased overall 5hmC levels, it also increased 5hmC distribution at certain mutation loci such as Arih2. Vitamin C treatment, which mimics Tet2/Tet3 restoration, blocked disease progression in Tet2-deficient NHD13 mice. Collectively, our findings demonstrate that TET2 activity governs occurrence of secondary mutations in MDS HSPCs, providing a rationale for enhancing TETs function to block MDS-malignant transformation.

2022-10-12 | GSE213591 | GEO

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