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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ChIP-seq]

ABSTRACT: To determine the impact of inhibition of KDM1A/LSD1 through genetic manipulation or with irreversible LSD1 inhibitors on global chromatin accessibility and occupancy of H3K27Ac and BRD4 in AML and post-MPN sAML cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160318 | GEO | 2021/05/26

REPOSITORIES: GEO

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ATAC-seq]

Project description:To determine the impact of inhibition of KDM1A/LSD1 through genetic manipulation or with irreversible LSD1 inhibitors on global chromatin accessibility and occupancy of H3K27Ac and BRD4 in AML and post-MPN sAML cells.

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [RNA-seq]

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells

Project description:Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ATAC-seq]

Project description:Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ATAC-seq]

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [RNA-seq]

Project description:Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [RNA-seq]

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ChIP-seq]

Project description:Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ChIP-seq]

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells

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

2021-05-26 | GSE160319 | GEO

Novel BET protein Proteolysis Targeting Chimera (BET-PROTAC) exerts superior lethal activity than Bromodomain Inhibitor (BETi) against post-myeloproliferative Neoplasm (MPN) Secondary (s) AML Cells

Project description:The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reversed Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in mRNA and protein expressions than OTX015 in sAML cells. Specifically, compared to OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, pSTAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared to OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against the established and PD-CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

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

Project description:This SuperSeries is composed of the following subset Series: GSE34672: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [Illumina HumanHT-12 gene expression array] GSE34725: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [ChIP-Seq] Refer to individual Series

2012-03-14 | E-GEOD-34726 | biostudies-arrayexpress

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.

Project description:There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.

| S-EPMC8138012 | biostudies-literature

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