Transcriptomic analysis of hyperglycemic stress induced myeloid neoplasms associated with Tet2 haploinsufficiency
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ABSTRACT:
PROVIDER: PRJNA664959 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12692227.fastq.gz | Fastqsanger.gz | |||
| SRR12692228.fastq.gz | Fastqsanger.gz | |||
| SRR12692229.fastq.gz | Fastqsanger.gz | |||
| SRR12692230.fastq.gz | Fastqsanger.gz | |||
| SRR12692231.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To identify potential mediators of myeloid neoplasms driven by Tet2 haploinsufficiency and hyperglycemic stress. Methods: Lin-negative bone marrow cells from WT, Tet2+/-, Ins2Akita/+ and Tet2+/-;Ins2Akita/+ were used for total RNA purification and RNA-seq. Results: Using unbiased Gene Set Enrichment Analysis (GSEA), we identified that innate immune pathway, IL-6 signaling pathway and TLR4-NFkB pathway were significantly enriched in the compound mutants (Tet2+/-;Ins2Akita/+) while controls (Tet2+/- or Ins2Akita/+) were similar to WT mice.
2020-09-23 | GSE158351 | GEO
Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation Gene expression profiles from WT and Tet2-/- sorted LSK and myeloid progenitors (CMP and GMP) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Mouse 430 2.0) and key targets were validated by chromatin immunoprecipitation experiments.
2011-07-01 | E-GEOD-27816 | biostudies-arrayexpress
Project description:Model describing how HOXA9 may control the evolution of myeloproliferative neoplasms by integrating the orders of JAK2 and TET2 mutation
2023-03-17 | MODEL2212110001 | BioModels
Project description:Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. We performed SNP array analysis on de novo and therapy-related myeloid neoplasms and identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage upon transplantation into immunodeficient mice. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms. We performed SNP-array analysis of 34 primary patient samples with de novo or therapy-related myeloid leukemia and one acute myeloid leukemia cell line, UoCM1. For patient samples, DNA was obtained from the white blood cells of bone marrow or peripheral blood leukemia specimens. Cytogenetic analysis revealed clonal -7/del(7q) in 17 of the cases.
2012-11-24 | E-GEOD-42482 | biostudies-arrayexpress
Project description:Abnormalities of chromosome 7q are common in myeloid malignancies. Agilent CGH arrays targeted to 7q and Affymetrix SNP 6.0 arrays were used to characterise 7q aUPD and deletions. Sample #017 in this data series showed a microdeletion encompassing EZH2. Screening of a total of 614 cases with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals, most commonly myelodysplastic/myeloproliferative neoplasms (27/219; 12%) and myelofibrosis (4/30; 13%). EZH2 encodes the catalytic subunit of the Polycomb repressive complex 2 (PRC2), the highly conserved histone H3 lysine 27 methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity and its overexpression has been causally linked to differentiation blocks in epithelial tumors. Unexpectedly, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies. High density CGH array analysis of 7q and the TET2 region in 8 atypical myeloproliferative neoplasms
2010-06-30 | E-GEOD-21948 | biostudies-arrayexpress
Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation
2011-07-01 | GSE27816 | GEO
Project description:Loss of function mutations inTET2(LOF) occur in up to 58% and 30% of myeloid malignancies and clonal hematopoiesis (CH) respectively. Genetically engineered murine models of Tet2 LOF display splenomegaly, granulomonocytic expansion, and increased bone marrow hematopoietic stem and progenitors. However, the direct downstream effectors of TET2 LOF leading to this phenotype are unknown. Using multiome single cell sequencing from a cohort of severe COVID patients with or without TET2 mutations we show that MALAT1, a therapeutically tractable long non-coding RNA, is overexpressed and is both necessary and sufficient to induce TET2 LOF phenotypes. We additionally demonstrate that TET2 LOF leads to decrease activity of the transcriptional repressor EGR1 leading to upregulation of MALAT1. This upregulation then leads to sustained NFkB activity by inhibiting the phosphatase activity of PP2A on P65 resulting in increased pro-inflammatory cytokines such as IL-6 required for TET2 LOF phenotypes in MALAT1 overexpressing mice
2024-08-13 | GSE243492 | GEO
Project description:Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. We performed SNP array analysis on de novo and therapy-related myeloid neoplasms and identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage upon transplantation into immunodeficient mice. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms.
2012-11-24 | GSE42482 | GEO
Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.
2020-09-09 | PXD020550 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE21948: High Density custom Agilent 44K CGH array analysis of 7q and TET2 region in myelodysplastic/myeloproliferative neoplasms GSE21990: Affymetrix SNP 6.0 array data for myelodysplastic/myeloproliferative neoplasms Refer to individual Series
2010-06-30 | E-GEOD-21991 | biostudies-arrayexpress