Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core

ABSTRACT: We investigated the combination of the irreversible LSD1 inhibitor T-3775440 and the JAK1/JAK2 inhibitor ruxolitinib as novel therapeutic approach in ML-DS which is specifically designed to target key hallmarks of ML-DS leukemogenesis. We observed synergistic anti-leukemic effects by combining both drugs. To elucidate the underlying molecular mechanisms we performed RNAseq in two independent patients samples treated with vehicle, LSD1 inhibitor or ruxolitinib monotherapy or the combination of both drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201093 | GEO | 2022/05/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

JAK/STAT blockade in cHL

Project description:Here we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor. We use five classical Hodgkin lymphoma cell lines: L428, L1236, L540, KMH2, L591

2021-10-15 | GSE185818 | GEO

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Project description:Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the pro-tumorigenic factor cyclooxygenase-2 (COX-2) and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a novel mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.

2019-05-16 | GSE131300 | GEO

Targeting Group3 Medulloblastoma by the anti-PRUNE-1 and anti-LSD1- KDM1A molecules augments their potential therapeutic value.

Project description:The combination of AA7.1 and SP2577 affects neuronal commitment,leukocyte differentiation and mitochondrial metabolism. To better dissect the mechanisms of action of these two drugs and to investigate the genes and pathways affected we treated primary Group3 MB for 24 hours with 100μM AA7.1 (pruneinhibotor) , 22.5μM SP2577 ( LSD1 inhibitor) and the combination and we performed RNA-Seq. Vehicle treated cells were used as control. Gene expression analysis showed up-regulation of genes implicated in neuronal differentiation, mitochondrial metabolism in cells treated with Prune-1 and LSD1 inhibitors, with stronger evidence in cells treated with the combination of two drugs.

2024-03-30 | E-MTAB-13616 | biostudies-arrayexpress

Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

Project description:The type I JAK inhibitor ruxolitinib is approved for therapy of MPN patients but evokes resistance with longer exposure. Several novel type I JAK inhibitors were studied and we show that they uniformly induce resistance via a shared mechanism of JAK family heterodimer formation.Here we studied the expression profiles of SET2 cell lines persistent to several different type I JAK inhibitors in comparison to naive SET2 cells or in comparison to SET2 cells with acute exposure to ruxolitinib. Analysis of RNA isolated from several type I JAK inhibitor SET2 cell lines in comparison to naïve SET2 cells

2015-07-11 | E-GEOD-69827 | biostudies-arrayexpress

Aberrant JAK-STAT pathway confers resistance to the HDAC inhibitor chidamide in Natural Killer/T-cell lymphoma through chromatin remodeling

Project description:Natural Killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with poor prognosis and limited therapeutic options. Here, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating relapsed/refractory NKTL patients, achieving an overall response rate of 39.3%, with 17.9% complete response rate. However, the clinical response to chidamide remains variable as more than half of the patients exhibit primary resistance, limiting its utility in NKTL treatment. To unravel the resistance mechanisms of chidamide, we performed integrative transcriptomic and chromatin profiling of sensitive and resistant NKTL cells. Our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Collectively, our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL.

2023-03-02 | GSE152185 | GEO

Transient JAK/STAT pathway inhibition prevents natural occurring B-ALL development in genetically predisposed Pax5+/- mice

Project description:We used microarrays to investigate gene expression changes in bone marrow B220+ cells from Pax5+/- and wild-type mice after ruxolitinib treatment during 2 weeks. Preventing development of B cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects in children, is a longstanding and unsolved challenge in medicine. In humans and mice, germline alterations in the Pax5 gene can lead to B-ALL. Preclinical studies have shown that this malignant transformation only occurs under an immune stress through the accumulation of secondary mutations in the JAK/STAT pathway. Here we describe that transient oral administration of ruxolitinib, a drug targeting the JAK/STAT pathway, can mitigate the risk of B-ALL in Pax5+/- mice. Although exposure to infection strongly potentiates leukemogenesis, the development of B-ALL was significantly impeded by transient in vivo treatment of Pax5+/- mice with ruxolitinib early in life (p-value=0.0332). These findings provided the first in vivo evidence for an effective preventive strategy for B-ALL development in genetically predisposed mice.

2021-07-02 | GSE179182 | GEO

Efficacy of JAK 1/2 inhibition in murine immune bone marrow failure

Project description:Background and methods: Ruxolitinib (RUX) is a Jak inhibitor that is used in the treatment of intermediate or high risk myelofibrosis and resistant forms of polycythemia vera and graft-vs-host disease due to its efficacy of reducing inflammatory cytokines and markers of inflammation. We tested its potential therapeutic effects in murine models of immune-mediated bone marrow failure. RNA-Seq and analysis was performed using NEBNext Ultra™ II RNA Library Prep Kit for Illumina and Illumina Novaseq6000, according to the Institute's protocols. Results: As both prophylaxis and therapy, Ruxolitinib improved pancytopenia and BM cellularity and decreased BM T cell infiltration in bone marrow failure mice. RNA sequencing demonstrated that Ruxolitinib suppressed expression of inflammtory genes in bone marrow infiltrated CD8 T cells compared with untreated mice. Conclusion: Our results demonstrate that Ruxolitinib is highly effective in attenuation of disease and extending survival of immune-mediated bone marrow failure mice.

2023-01-29 | GSE196645 | GEO

Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

2015-07-11 | GSE69827 | GEO

Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core.

Project description: Not available

| S-EPMC9252908 | biostudies-literature

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project4]

Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.

2023-10-04 | GSE244282 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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