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SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

ABSTRACT: SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

PROVIDER: PRJNA481954 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7540950.fastq.gz	Fastqsanger.gz
	SRR7540951.fastq.gz	Fastqsanger.gz
	SRR7540952.fastq.gz	Fastqsanger.gz
	SRR7540953.fastq.gz	Fastqsanger.gz
	SRR7540948.fastq.gz	Fastqsanger.gz

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SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [microarray expression profiling]

Project description:Improved understanding of mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. We revealed a novel regulatory axis that SIRT1-deficiency induced TET2 hyperacetylation promotes MDS HSPC functions, and provide an approach to target MDS HSPCs by activating SIRT1 deacetylase. Four Groups: Group1: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for SIRT1); Group2: MDS-L cells transduced with lentiviral vector containing interference squence targeting SIRT1 (SIRT shRNA); Group 3: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for TET2); Group 4: MDS-L cells transduced with lentiviral vector containing interference squence targeting TET2 (TET2 shRNA).

2018-08-13 | GSE117272 | GEO

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [hMeDIP-Seq]

2018-08-13 | GSE117363 | GEO

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [hMeDIP-Seq]

Project description:SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [hMeDIP-Seq]

| PRJNA481884 | ENA

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [microarray expression profiling]

Project description:SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [microarray expression profiling]

| PRJNA481584 | ENA

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function.

Project description:Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is derived from aberrant clonal hematopoietic stem/progenitor cells (HSPCs) that persist after conventional therapies. Defining the mechanisms underlying MDS HSPC maintenance is critical for developing MDS therapy. The deacetylase SIRT1 regulates stem cell proliferation, survival, and self-renewal by deacetylating downstream proteins. Here we show that SIRT1 protein levels were downregulated in MDS HSPCs. Genetic or pharmacological activation of SIRT1 inhibited MDS HSPC functions, whereas SIRT1 deficiency enhanced MDS HSPC self-renewal. Mechanistically, the inhibitory effects of SIRT1 were dependent on TET2, a safeguard against HSPC transformation. SIRT1 deacetylated TET2 at conserved lysine residues in its catalytic domain, enhancing TET2 activity. Our genome-wide analysis identified cancer-related genes regulated by the SIRT1/TET2 axis. SIRT1 activation also inhibited functions of MDS HSPCs from patients with TET2 heterozygous mutations. Altogether, our results indicate that restoring TET2 function through SIRT1 activation represents a promising means to target MDS HSPCs.

| S-EPMC6143172 | biostudies-literature

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

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

2018-08-13 | GSE117383 | GEO

Myelodysplastic/myeloproliferative neoplasms

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

Acquired mutations in TET2 are common in myelodysplastic syndromes

Project description:Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we performed SNP-array-based genomic profiling and genomic sequencing in 102 patients. We identified acquired deletions, missense and nonsense mutations in a new gene, TET2, in 26% of MDS patients. Using allele-specific assays, TET2 mutations were shown to be present in the majority of the myeloid cells (56-100%, median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34+ progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.

2009-05-28 | GSE15688 | GEO

Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

Project description:Mutations in the TET2 gene are frequent in myeloid disease, although their biological and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using ‘Next-Generation’ sequencing (NGS) for TET2 aberrations; 91 of whom were also subjected to SNP6 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) ≥10%, were identified in 39 of 320 (12%) MDS and 16 of 35 (46%) CMML patients (p<0.001). Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. ‘Deeper’ sequencing of 96 patient samples identified 4 additional mutations (RMA 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells in addition to CD34+ and total bone-marrow cells (23.5%, 38.5% and 43% RMA respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression or the JAK2V617F 46/1 haplotype between TET2-mutated and non-mutated patients. There was no significant prognostic association between TET2 mutations and WHO subtypes, IPSS score, cytogenetic status, or transformation to AML. On multivariate analysis, age (>50yrs) was associated with a higher incidence of TET2 mutation (p=0.02). Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from bone marrow or peripheral blood samples. Copy number and acquired UPD analysis of Affymetrix SNP 6.0 arrays was performed for 91 cases with Myelodysplastic syndromes.

2010-07-30 | E-GEOD-23300 | biostudies-arrayexpress

Context Dependent Effects of Ascorbic Acid Treatment in TET2 Mutant Myeloid Neoplasia

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

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