Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Anti-leukemic effect of TGN-1062, a novel CDK7 inhibitor, on AML-leukemic stem cells by targeting RNA modification and Mitochondrial metabolism

ABSTRACT: Anti-leukemic effect of TGN-1062, a novel CDK7 inhibitor, on AML-leukemic stem cells by targeting RNA modification and Mitochondrial metabolism

PROVIDER: PRJNA1188203 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR31403079_1.fastq.gz	Fastqsanger.gz
	SRR31403079_2.fastq.gz	Fastqsanger.gz
	SRR31403080_1.fastq.gz	Fastqsanger.gz
	SRR31403080_2.fastq.gz	Fastqsanger.gz
	SRR31403081_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 24

Similar Datasets

Anti-leukemic effect of TGN-1062, a novel CDK7 inhibitor, on AML-leukemic stem cells by targeting RNA modification and Mitochondrial metabolism

Project description:High expression of CDK7, a cell cycle regulator and transcriptional modulator, correlates with poor outcomes in acute myeloid leukemia (AML). We report that TGN-1062, a novel CDK7 inhibitor, exhibits significant antileukemic effects by inhibiting cell growth and inducing apoptosis in AML cell lines and primary CD34+CD38- blasts (enriched for leukemia stem cells; LSCs), while sparing normal CD34+CD38- cells (enriched for hematopoietic stem cells; HSCs). Our study revealed that TGN-1062 treatment in primary CD34+CD38- AML blasts suppress RNA m6A modification by downregulating METTL3/14 proteins, key components of the m6A methyltransferase complex that regulate RNA stability and translation. Decrease in METTL proteins reduced BCL-2 m6A RNA modification and led to increased BCL-2 mRNA decay and protein levels. BCL-2 downregulation resulted in disruption of mitochondrial metabolism and mitofusion in LSCs through decrease of HMGB1/HSPB1 and NRF2/DRP1 signaling, respectively. In vivo, TGN-1062 significantly reduced leukemia burden and prolonged survival in a murine MllPTD/WT/Flt3ITD/ITD AML model and in FLT3-WT and inv(16) AML patient-derived xenografts (PDXs). Increased survival in secondary transplant experiments supported TGN-1062 activity on LSCs. Of note, we proved that TGN-1062 synergized with the BCL-2 inhibitor, venetoclax in eliminating LSCs in both murine and PDX AML models, underscoring its potential as a promising therapeutic approach for AML patients.

2024-11-24 | GSE282364 | GEO

Effect of CDK7 inhibitor on protein expression alterations in cultured secondary AML HEL92.1.7 cells

Project description:HEL92.1.7 cells in exponential growth phase were treated with 100 nM of SY-5609 for 24 hours to determine the global protein expression alterations that correlate with the cell cycle, growth inhibitory and lethal effects of treatment with a CDK7 inhibitor in secondary AML cells.

2025-04-28 | PXD053572 | Pride

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones

Project description:Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML. This SuperSeries is composed of the SubSeries listed below.

2016-11-14 | GSE89778 | GEO

Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

Project description:Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

| PRJNA814710 | ENA

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [methylation]

2016-11-14 | GSE89776 | GEO

Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

Project description:The tracking of leukemic clones in acute myeloid leukemic promisses deeper insights into disease development and therapeutic options. We therefore established a fluorescent genetic barcoding (FGB) labeling approach that allows for flow cytomtric tracking of color-coded clones in vitro and in vivo. In Hoxa9 and Meis1 (H9M) dependent murine AML, we tracked the growth behavior of 24 clones in parallel and enriched for pre-leukemic clones as well as their de novo expanded counterparts and stably expanded clones from leukemic mice by fluorescence-activated cell sorting. These samples were subjected toRNA sequencing for the assessment of transcriptional changes underlying clonal maintenance and expansion.

2022-12-28 | GSE198371 | GEO

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [RNA-seq]

2016-11-14 | GSE89777 | GEO

Human TFIIH kinase CDK7 regulates transcription-associated epigenetic modification

Project description:CDK7 phosphorylates the RNA polymerase II (pol II) CTD and activates the P-TEFb- associated kinase, CDK9, but its regulatory roles remain obscure. Using human CDK7 analog-sensitive (CDK7as) cells, we observed reduced capping enzyme recruitment, increased pol II promoter-proximal pausing, and defective termination at gene 3'-ends upon CDK7 inhibition. We also found that CDK7 regulates chromatin modifications downstream of transcription start sites. H3K4me3 spreading was restricted at gene 5'-ends and H3K36me3 was displaced toward gene 3'-ends in CDK7as cells. Together, these results implicate a CDK7-dependent "CTD code" that regulates epigenetic marks in addition to RNA processing and pol II pausing.

2017-08-01 | GSE100040 | GEO

Genome-wide maps of chromatin state in primary MLL-AF9 AML

Project description:Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly-gained SEs in primary mouse AML cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis.

2018-08-23 | GSE117443 | GEO

Effect of CDK7 inhibitor, FHD-286, SNDX-50469, or Tasquinimod on protein expression alterations in patient-derived secondary AML or de novo MLL1-rearranged AML cells

Project description:Patient-derived secondary AML cells were treated with 100 nM of SY-5609 for 24 hours, 100 nM of FHD-286 for 48 hours, or 20 µM of Tasquinimod for 48 hours to determine the global protein expression alterations that correlate with the cell cycle, growth inhibitory and lethal effects of treatment with a CDK7 inhibitor, chromatin remodeling inhibitor, or S100A8/S100A9 inhibitor or in secondary AML cells. Patient-derived de novo AML cells with MLL1 rearrangement and Menin T349M mutation were treated with 100 nM of FHD-286 or 500 nM SNDX-50469 for 48 hours to determine the global protein expression alterations that correlate with the cell cycle, growth inhibitory and/or lethal effects of treatment with a chromatin remodeling inhibitor, FHD-286, or a Menin inhibitor SNDX-50469 in MLL1 rearranged AML cells

2025-04-28 | PXD053548 | Pride

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