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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]

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

PROVIDER: PRJNA672921 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12924600_1.fastq.gz	Fastqsanger.gz
	SRR12924600_2.fastq.gz	Fastqsanger.gz
	SRR12924601_1.fastq.gz	Fastqsanger.gz
	SRR12924601_2.fastq.gz	Fastqsanger.gz
	SRR12924602_1.fastq.gz	Fastqsanger.gz

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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: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 [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

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

| PRJNA672936 | ENA

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 [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

Pre-clinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms (MPN) transformed to AML

Project description:Rising blast-percentage or secondary (s) AML transformation (sAML) in MPNs leads to JAK inhibitor (JAKi) therapy-resistance and poor survival. Here, we demonstrate that the CDK7 inhibitor (CDK7i) SY-5609 treatment depletes phenotypically-characterized post-MPN-sAML stem/progenitor cells. In the cultured post-MPN sAML SET2 and HEL as well as patient-derived (PD) post-MPN-sAML cells, SY-5609 treatment inhibited growth and induced lethality, while sparing normal cells. RNA-Seq analysis following SY-5609 treatment demonstrated reduced mRNA expressions of MYC, MYB, CDK4/6, PIM1, and CCND1, but increased mRNA levels of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also demonstrated reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase 9 and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced viability of HEL cells. CyTOF analysis of SY-5609-treated PD, post-MPN-sAML stem/progenitor cells showed reduced c-Myc, CDK6 and PU.1, but increased protein levels of CD11b, p21 and cleaved Caspase 3. Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells.  A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML.

2025-02-19 | GSE277035 | GEO

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

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

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [microarray]

Project description:Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.

2018-12-07 | GSE123409 | GEO

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