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Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation (RNA-Seq)

ABSTRACT: Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation (RNA-Seq)

PROVIDER: PRJNA1055693 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27320185_1.fastq.gz	Fastqsanger.gz
	SRR27320185_2.fastq.gz	Fastqsanger.gz
	SRR27320186_1.fastq.gz	Fastqsanger.gz
	SRR27320186_2.fastq.gz	Fastqsanger.gz
	SRR27320187_1.fastq.gz	Fastqsanger.gz

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Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Project description:Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

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Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation (CUT&RUN)

Project description:Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation (CUT&RUN)

| PRJNA1055694 | ENA

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation (RNA-Seq)

Project description:Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.

2025-01-09 | GSE251859 | GEO

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation (CUT&RUN)

2025-01-09 | GSE251857 | GEO

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

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

2025-01-09 | GSE251860 | GEO

Deficiency of ERO1 and activation of protein translation synergistically impair breast tumor resilience

Project description:Endoplasmic reticulum (ER) stress triggers an adaptive response which fosters tumor cell survival and resilience to stress conditions. Activation of the endoplasmic reticulum stress response, through its PERK branch, promotes the phosphorylation of the α-subunit of translation initiation factor eIF2alpha, thereby repressing general protein translation and selectively augmenting the translation of ATF4 with the downstream CHOP transcription factor and the protein disulfide oxidase ERO1. Here, we show that ISRIB, a small molecule, which inhibits the action of the phosphorylated α-subunit of eIF2, thereby activating protein translation, synergistically interacts with the genetic deficiency of protein disulfide oxidase ERO1 enfeebling tumor growth and spreading. ISRIB represses CHOP signal but surprisingly does not inhibit ERO1. Mechanistically, ISRIB increases the ER protein load with a prominent perturbing effect on ERO1 deficient Triple-Negative breast cells, which have adapted to live with low client protein load, while ERO1 deficiency selectively impairs VEGF-dependent angiogenesis. Strikingly, ERO1-deficient Triple Negative Breast Cancer xenografts have augmented ER stress response and PERK branch. In vivo, ISRIB synergistically with ERO1 deficiency inhibits the growth of Triple-Negative Breast cancer xenografts by impairing proliferation and angiogenesis, while it is not effective on the xenograft counterparts with ERO1. In summary, these results demonstrate that ISRIB together with ERO1 deficiency synergistically shatters a feature of the adaptive ER stress response while ERO1 deficiency selectively impairs angiogenesis in tumors, thereby together promoting tumor cytotoxicity. Therefore, our findings suggest two surprising findings in breast tumors: ERO1 is not regulated via CHOP and ISRIB represents a therapeutic option to efficiently inhibit tumor progression in those tumors with limited ERO1 and high PERK.

2022-07-20 | E-MTAB-11313 | biostudies-arrayexpress

LSD1 complexes - Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Project description:Lsd1 ablation triggers metabolic reprogramming of brown adipose tissue. Lsd1 protein complexes were purified from mouse adipose tissue and analyzed by label-free LC-MS/MS. Mice were kept under different conditions prior complex isolation.

2017-01-03 | PXD004745 | Pride

Simultaneous Inhibition of LSD1 and TGF-β Enables Eradication of Poorly Immunogenic Tumors with anti-PD-1 Treatment

Project description:Epigenetic regulators are a class of promising targets in the combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGF-β expression, which exerts an inhibitory effect on T cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation-induced T cell infiltration. Importantly, concurrent depletion of LSD1 and TGF-β in combination with PD-1 blockade significantly increases both CD8+ T cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor re-challenge. Thus, combining LSD1 inhibition with blockade of TGF-β and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors.

2021-03-09 | GSE161569 | GEO

LSD1 interactome in Glioblastoma

Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.

2022-06-02 | PXD021429 | Pride

Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [anti-LSD1, MYB, and GFI1 ChIP-Seq]

Project description:To identify genomic binding regions, THP1 AML cells were subjected to ChIP sequencing (ChIPseq) using anti-LSD1, MYB or GFI1 antibodies.

2018-03-27 | GSE90769 | GEO

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