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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160319 | 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 [ChIP-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.

2021-05-26 | GSE160318 | GEO

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

2021-05-26 | GSE160309 | GEO

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

Project description:To determine the impact of inhibition of KDM1A/LSD1 through genetic manipulation by CRISPR/Cas9 or inducible shRNA or following treatment with irreversible LSD1 inhibitor INCB059872 on global transcriptomic profile in AML and post-MPN sAML cells. To determine the impact of GFI1 knockdown on global transcriptomic profile in AML cells.

2021-05-26 | GSE160303 | GEO

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

| PRJNA672936 | ENA

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

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]

| PRJNA672931 | ENA

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]

| PRJNA672921 | ENA

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]

| PRJNA672943 | ENA

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.

2017-04-06 | GSE93578 | GEO

KDM1A inhibition augments the efficacy of rapamycin for the treatment of endometrial cancer.

Project description:Endometrial cancer (EC) often exhibit aberrant activation of PI3K/Akt/mTOR signaling and targeted therapies using mTOR inhibitors showed limited success. The epigenetic modifier, lysine-specific histone demethylase-1A (KDM1A/LSD1) is overexpressed in EC, however, the mechanistic and therapeutic implications of KDM1A in EC are poorly understood. Here, using 119 FDA-approved drugs screen, we identified that KDM1A inhibition is highly synergistic with mTOR inhibitors. Combination therapy of KDM1A and mTOR inhibitors potently reduced the cell viability, survival, and migration of EC cells. Mechanistic studies demonstrated that KDM1A inhibition attenuated the activation of mTOR signaling cascade and abolished rapamycin induced feedback activation of Akt. RNA-seq analysis identified that KDM1A inhibition downregulated the expression of genes involved in rapamycin induced activation of Akt, including the mTORC2 complex. Chromatin immunoprecipitation experiments confirmed KDM1A recruitment to the promoter regions of mTORC2 complex genes and that KDM1A inhibition promoted enrichment of repressive H3K9me2 marks at their promoters. Combination therapy of KDM1A inhibitor and rapamycin reduced the tumor growth in EC xenograft and patient derived xenograft models in vivo and patient derived tumor explants ex vivo. Importantly, in silico analysis of TCGA EC patients data sets revealed that KDM1A expression positively correlated with the levels of PI3K/Akt/mTOR genes. Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.

| S-EPMC10000284 | biostudies-literature

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