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Effects of crizotinib on gene expression profiles of cultured hematopoietic stem and progenitor cells (HSPCs) derived from MDS mice

ABSTRACT: Effects of crizotinib on gene expression profiles of cultured hematopoietic stem and progenitor cells (HSPCs) derived from MDS mice

PROVIDER: PRJNA1113698 | ENA |

REPOSITORIES: ENA

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Effects of crizotinib on gene expression profiles of cultured hematopoietic stem and progenitor cells (HSPCs) derived from MDS mice

Project description:Myelodysplastic syndromes are characterized by bone marrow (BM) failure due to ineffective hematopoiesis. However, the underlying mechanisms of ineffective hematopoiesis, in which clonal expansion coexists with accelerated cell death, remain to be elucidated. Recently, we established the CBLΔE8/9/RUNX1S291fs mice (MDS mice), which develope a variety of MDS phenotypes including defects in megakaryocyte (MK) maturation. We identified crizotinib as a potent inducer of MK maturation. RNA-Seq of cultured HSPCs derived from the mice revealed that crizotinib increased the expression levels of MK and platelet-related genes.

2025-08-15 | GSE267954 | GEO

Transcriptomes of CD34+ hematopoietic stem/progenitor cells (HSPCs) from myelodysplastic syndromes (MDS) patients cultured in normoxia or hypoxia.

Project description:Transcriptomes of CD34+ hematopoietic stem/progenitor cells (HSPCs) from myelodysplastic syndromes (MDS) patients cultured in normoxia or hypoxia.

| PRJNA723832 | ENA

Transcriptomes of CD34+ hematopoietic stem/progenitor cells (HSPCs) from myelodysplastic syndromes (MDS) patients cultured in normoxia or hypoxia.

Project description:Three MDS patients (SF3B1mut -H662/H662/Q699) and three age-matched healthy donors were challenged in colony forming assay under normoxic (20% O2) and hypoxic (3% O2) conditions. RNA-sequencing was performed on the HSPC-derived colonies o examine transcriptional changes under normoxic and hypoxic conditions.

2023-03-01 | GSE173108 | GEO

ROBO1 deficiency impairs hematopoietic stem progenitor cell self-renewal and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Project description:We previously identified inactivating mutations in roundabout guidance receptor 1 (ROBO1) in patients with myelodysplastic syndrome (MDS), which was associated with poor prognosis and susceptibility to acute myeloid leukemia (AML) transformation. Nonetheless, the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here we report that the ablation of Robo1 in mice is sufficient to confer MDS-like disease with anemia and multilineage dysplasia. More specifically, Robo1 deficiency impairs the self-renewal and differentiation capacity of hematopoietic stem progenitor cells (HSPCs) and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors (MEPs), which causes a blockage in the early stages of erythropoiesis in mice. Similarly, Robo1-deficienct HSPCs recapitulated MDS-like disease with anemia and multilineage dysplasia in transplanted mice. Correspondingly, clinical data also reveal that low expression of ROBO1 is associated with shortened survival, severe anemia and a high risk of AML transformation in patients with MDS. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-GTPase family, serves as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the proliferation of erythroid colonies in Robo1 deficient mice. In contrast, Cdc42 inhibitor (CASIN) effectively attenuates the erythroid colony formation of HSPCs. Collectively, our results suggest that Robo1 deficiency may provide a promising therapeutic target against MDS by impairing HSPC self-renewal and erythropoiesis via CDC42, predicting a poor prognosis for severe anemia and a high risk of AML transformation in MDS.

2023-12-01 | GSE231641 | GEO

Foetal and adult HSPCs - Comprehensive Proteomic Characterization of Ontogenic Changes in Hematopoietic Stem and Progenitor Cells

Project description:Haematopoietic stem and progenitor cells (HSPCs) in the foetus and adult possess distinct molecular landscapes that regulate cell fate and change their susceptibility to initiation and progression of haematopoietic malignancies. The proteomic programs that govern these differences remain elusive. In this study, we have utilized a mass spectrometry-based quantitative proteomics approach to comprehensively describe and compare the proteome of foetal and adult HSPCs. We found that the proteome of foetal HSPCs is relatively simple, characterized by proteins involved in cell cycle and cell proliferation, while their adult counterparts are defined by a larger set of proteins that are involved in more diverse cellular processes. These adult characteristics include an arsenal of proteins important for viral and bacterial defence, as well as protection against ROS-induced protein oxidation. Our further analyses of Type I interferon signalling shows that foetal HSPCs are sensitive to Interferon a (IFNa), which impairs their production of mature lymphoid cells, whereas stimulation with IFNa to the pregnant mother enhances the production of early progenitors from foetal HSCs. Our results provide new and important insights into the molecular landscape of foetal and adult haematopoiesis that advance our understanding of normal and malignant haematopoiesis during foetal and adult life.

2017-12-12 | PXD006876 | Pride

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.

2022-03-08 | GSE184246 | GEO

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.

2017-03-15 | GSE79204 | GEO

Chromatin accessibility of hematopoietic stem/progenitor cells (HSPCs) derived from MDS patients before and after disease progression

Project description:Myelodisplastic syndromes are a oligoclonal disease starting at the level of the stem/progenitor compartment. We used ATACseq to determine changes in chromating landscape between MDS low and high risk samples.

2025-06-02 | GSE298729 | GEO

Project description:Quantification of apoptosis-related genes in bone marrow HSPCs from MDS patients compared to healthy donor by microfluidic cards

2016-11-07 | GSE89579 | GEO

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.

2019-09-30 | GSE119916 | GEO

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