Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

47 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Methylation profiling by array shows that mIDH-associated DNA hypermethylation in acute myeloid leukemia reflects differentiation blockage rather than inhibition of TET-mediated demethylation

ABSTRACT: Isocitrate dehydrogenases 1 and 2 (IDH1/2) are recurrently mutated in acute myeloid leukemia (AML), but their mechanistic role in leukemogenesis is poorly understood. The inhibition of TET enzymes by D-2-hydroxyglutarate (D-2-HG), which is produced by mutant IDH1/2 (mIDH1/2), has been suggested to promote epigenetic deregulation during tumorigenesis. In addition, mIDH also induces a differentiation block in various cell culture and mouse models. Here we analyze the genomic methylation patterns of AML patients with mIDH using Infinium 450K data from a large AML cohort and found that mIDH is associated with pronounced DNA hypermethylation at tens of thousands of CpGs. Interestingly, however, myeloid leukemia cells overexpressing mIDH, cells that were cultured in the presence of D-2-HG or TET2 mutant AML patients did not show similar methylation changes. In further analyses, we also characterized the methylation landscapes of myeloid progenitor cells and analyzed their relationship to mIDH-associated hypermethylation. Our findings identify the differentiation state of myeloid cells, rather than inhibition of TET-mediated DNA demethylation, as a major factor of mIDH-associated hypermethylation in AML. Furthermore, our results are also important for understanding the mode of action of currently developed mIDH inhibitors.

ORGANISM(S): Homo sapiens

SUBMITTER: Laura Wiehle

PROVIDER: E-MTAB-6059 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Profiling of ADAM12S regulated proteins in H1688 cells

Project description:In this project, we used SILAC quantitative proteomics to identify proteins that are differentially regulated by the short secreted form of A Disintegrin And Metalloproteinase 12, ADAM12S, in a small cell lung cancer cell line H1688. The aim of this study is to discover the proteins that are responsible for the cell proliferation, migration, and invasion and then to elucidate the molecular mechanism by which ADAM12S promotes these processes in small cell lung cancer cells.

2021-02-15 | PXD013242 | Pride

SILAC quantification of proteins in the control and UFBP1-expressing MGC803 cells

Project description:In this project, we used SILAC quantitative proteomics to identify proteins that are differentially regulated by UFM1-binding and PCI domain-containing protein 1 (UFBP1, also called DDRGK domain-containing protein 1 or DDRGK1) in a gastric cancer cell line. The aim of this study is to discover the proteins that are responsible for the biological function of UFBP1.

2021-02-15 | PXD013590 | Pride

RNA-seq of human SH-EP neuroblastoma cell line with SOX11 overexpression as compared to control at 9h timepoint

Project description:RNA-seq to define downstream targets of adrenergic SOX11 upon 1ug/ml doxycyline inducible SOX11 overexpression in a SOX11 non-expressing mesenchymal cell line SH-EP. Analysis was performed 48h upon treatment with doxycycline, control samples are the untreated cells. 2 biological replicates were used.

2022-12-13 | E-MTAB-11892 | biostudies-arrayexpress

RNA-seq of human SH-EP neuroblastoma cell line with SOX11 overexpression as compared to control

2022-12-13 | E-MTAB-9338 | biostudies-arrayexpress

ATAC-seq of human SH-EP neuroblastoma cell line with SOX11 overexpression as compared to control

Project description:ATAC-seq to define open and closed chromatin in the human SH-EP neuroblastoma cell upon 1ug/ml doxycyline inducible SOX11 overexpression. Analysis was performed 48h upon treatment with doxycycline, control samples are the untreated cells. 3 biological replicates from different monoclonal expansions of SH-EP cells were used.

2023-12-30 | E-MTAB-11898 | biostudies-arrayexpress

Dynamic transcriptomes of human myeloid leukemia cells

Project description:To identify the mechanisms controlling chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) in humans, we analyzed genome-wide transcription dynamics in three myeloid leukemia cell lines (K562, HL-60, and THP1) using high-throughput sequencing technology. Using KEGG analysis, we found that the ERK/MAPK, JAK-STAT and ErbB pathways promoted proliferation and metabolism in CML. However, in AML, differentiation and apoptosis blocking resulted in the accumulation of blast cells in marrow. In addition, each cell type had unique characteristics. K562 cells are an ideal model for studying erythroid differentiation and globin gene expression. The chemokine signaling pathway and Fc gamma R-mediated phagocytosis were markedly upregulated in HL-60 cells. In THP1 cells, highly expressed genes ensured strong phagocytosis by monocytes. Further, we provide a new insight into myeloid development. The abundant data sets and well-defined analysis methods will provide a resource and strategy for further investigation of myeloid leukemia. Compare mRNA transcriptomes of three different cell lines

2013-10-09 | E-GEOD-46164 | biostudies-arrayexpress

SDH deficiency-driven succinate accumulation dictates the drug resistance of AML through regulating p-UBC12/cullin activity

Project description:Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct microenvironment-associated metabolic processes. Here, we identified SDH deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to a wide range of anti-cancer therapies. Mechanistically, succinate promoted the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function was mediated by succinate-triggered upregulation of UBC12 phosphorylation, which impaired its E2 function in cullins neddylation. Notably, decreasing succinate levels by fludarabine could effectively restore the drug sensitivity of SDH-deficient AML PDX. Together, we uncover a novel function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.

2024-08-28 | PXD053722 | Pride

SDH deficiency-driven succinate accumulation dictates the drug resistance of AML through regulating p-UBC12/cullin activity

2024-08-28 | PXD047175 | Pride

Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [ChIP-Seq]

Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. ChIP-seq was used to study the effects of ATRA, TCP and ATRA/TCP treatment on H3K4 dimethylation. In addition to the three treatment samples, two reference samples were processed: (i) An untreated sample using the same anti-H3K4me2 antibody and an untreated sample using IgG. These five sequencing experiments were conducted using HL-60 cells and TEX cells, leading to 10 ChIP-seq samples in total.

2012-03-14 | E-GEOD-34725 | biostudies-arrayexpress

Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [Illumina HumanHT-12 gene expression array]

Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. Overall, 30 specimens derived from HL-60 or TEX cell line were treated with drugs and hybridized to Illumina HumanHT-12 gene expression arrays.

2012-03-14 | E-GEOD-34672 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data