Apoptosis-related gene expression profiling in hematopoietic cell fractions of MDS patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89579 | GEO | 2016/11/07
SECONDARY ACCESSION(S): PRJNA352625
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC5130187 | biostudies-literature
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
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 | GSE213530 | GEO
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
Project description:Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia.
2020-07-02 | GSE129691 | GEO
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
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
Project description:The MLL-PTD mutation is found in patients with MDS and AML, and not in other hematological malignancies. Previously, we showed that Mll-PTD knock-in heterozygous mice (MllPTD/WT mice) present with several MDS-associated features. However, these phenotypes are insufficient to constitute bona fide MDS. MllPTD/WT mice do not generate MDS or AML in primary or transplant recipient mice. This suggests that additional genetic and/or epigenetic defects are necessary for transformation to MDS or AML. In secondary AML and de novo AML, MLL-PTD mutation is significantly associated with mutations in RUNX1 and with the FLT3-ITD mutations. In fact, the combination of MLL-PTD with the FLT3-ITD allele leads to AML in mice. We combined the MLL-PTD with RUNX1 mutant proteins, in order to generate a new mouse model for MDS. We generated MllPTD/WT/Runx1Flox/Flox/Mx1-Cre mice to model loss-of-function RUNX1 mutations. To test the significance of HIF-1α in this model, we also generated MllPTD/WT/Runx1Flox/Flox/Hif-1αFlox/Flox/Mx1-Cre mice and genetically eliminated Hif-1α expression. We analyzed gene expression variations in the HSPCs comparing the MllPTD/WT/Runx1∆/∆ with or without HIF-1α abrogation.
2018-12-23 | GSE86953 | GEO
Project description:Altered bone marrow hematopoiesis and immune suppression is a hallmark of myelodysplastic syndrome (MDS). While the bone marrow microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from MDS patients compared to similar aged matched normal controls for regulation of immune function. MSCs from MDS patients (MDS-MSC) and healthy donor MSC (HD-MSC) exhibited a similar in vitro phenotype and neither had a direct effect on NK cell function. However, when MDS and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A unique MSC transcriptome was observed in MDS-MSCs compared to HD-MSCs, including increased expression of the reactive oxygen species (ROS) regulator, ENC1. High ENC1 expression in MDS-MSC induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF? superfamily of proteins. These monocytes also had reduced expression of the TGF? transcriptional repressor MAB21L2, further adding to their immune suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC conditioned monocytes mimicked the MDS-MSC suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune suppressive microenvironment in MDS through an indirect mechanism involving monocytes.
2020-02-11 | GSE140101 | GEO
Project description:To characterize the molecular changes in myelodysplastic syndromes (MDS) and to explore novel genetic abnormalities occurring in these disorders through a genome-wide study in a series of MDS and MDS/MPN patients. A total of 285 abnormalities were identified in 71 patients. Three high-risk MDS cases displayed chromothripsis. In addition, cryptic deletions were identified in genomic regions where MDS-related genes, such as DNMT3A (2p23.3), TET2 (4q24), RUNX1 (21q22) and BCOR (Xp11.4), are located.
2016-11-21 | GSE67682 | GEO