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Transcriptomic analysis of LSD1i-sensitive and resistant AML cells

ABSTRACT: The goal of this study is to identify the molecular mechanisms underlying the resistance/sensitivity of AML cells to lysine specific demethylase 1 (LSD1) inhibitor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125719 | GEO | 2020/01/26

REPOSITORIES: GEO

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LSD1 inhibition exerts its anti-leukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML [ChIP-seq]

Project description:Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML. We performed a comparative assessment of chromatin dynamics during the treatment of MLL-AF9-driven murine leukemias and MLL-rearranged patient-derived xenografts using two distinct but effective differentiation-inducing targeted epigenetic therapies, the LSD1 inhibitor GSK-LSD1 and the DOT1L inhibitor EPZ4777. Intriguingly, GSK-LSD1 treatment caused global gains in chromatin accessibility, whereas treatment with EPZ4777 caused global losses in accessibility. We captured PU.1 and C/EBPα motif signatures at LSD1 inhibitor-induced dynamic sites and ChIP-seq revealed co-occupancy of these myeloid transcription factors at these sites. Functionally, we confirmed that diminished expression of PU.1 or genetic deletion of C/EBPα in MLL-AF9 cells generates resistance of these leukemias to LSD1 inhibition. These findings reveal that pharmacologic inhibition of LSD1 represents a unique path to overcome the differentiation block in AML for therapeutic benefit.

2018-06-25 | GSE100758 | GEO

LSD1 inhibition exerts its anti-leukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML [ATAC-seq]

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RNA-seq of MV-4-11 or THP-1 cells treated with LSD1 inhibitor INCB059872

Project description:INCB059872 is a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1) that is in phase 1 clinical trials in hematopoietic malignancies. LSD1 inhibition can induce differentiation of acute myeloid leukemia (AML), and here we have used RNA-seq to measure the transcriptional changes caused by INCB059872 in two AML cell lines.

2020-05-28 | GSE145106 | GEO

Genome-wide CRISPR-Cas9 screen identifies druggable synthetic lethality between LSD1 and MTORC1 in MLL-translocated AML

Project description:Lysine Specific Demethylase 1 (LSD1 or KDM1A) is one of a number of epigenetic regulators which have recently emerged as candidate therapeutic targets in acute myeloid leukaemia (AML). Pharmacological inhibitors of LSD1 such as the tranylcypromine derivatives have already commenced evaluation in early phase clinical trials; however like all acute leukaemia therapies, it is unlikely that these inhibitors are effective as single agents. Therefore, there is a strong rationale to identify proteins that collaborate with LSD1 to maintain the leukemic phenotype and could be targeted in combination with LSD1 for enhanced therapeutic benefit. Using a genome-wide CRISPR-Cas9 dropout screen in human THP1 cells, we identified multiple regulatory components of the amino acid sensing arm of mTORC1 signalling - RRAGA, MLST8, and LAMTOR2 – as synthetic lethalities with LSD1 inhibition. Genetic and/or pharmacologic inhibition of selected genes in combination with LSD1 inhibition showed significant anti-leukemic activity by inducing a more extensive and wide-ranging myeloid differentiation program and reducing cell proliferation in THP1 and primary human AML cells in vitro and in vivo. In conclusion, we report that inhibition of mTORC1 sensitizes human MLL-translocated AML cells to LSD1 inhibitor-mediated differentiation therefore highlighting a novel combination approach for evaluation in clinical trials.

2019-12-23 | GSE126486 | GEO

Transcriptomic analysis of LSD1i-sensitive and resistant AML cells

Project description:Transcriptomic analysis of LSD1i-sensitive and resistant AML cells

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Synergistic Interaction Between the LSD1 Inhibitor T-3775440 and the NEDD8-activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) Promotes Anti-Acute Myeloid Leukemia Effects

Project description:Lysine-specific demethylase 1A (LSD1) specifically demethylates di- and monomethylated histone H3K4 or K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models.The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation and suppression of the leukemic stem cell gene signature.

2017-06-30 | GSE89637 | GEO

PU.1 and MYC transcriptional network defines a synergist drug response to combined KIT and LSD1 inhibition in acute myeloid leukemia

Project description:KIT mutant acute myeloid leukemia (AML) confers a worse prognosis for patients in a subtype of AML that has an otherwise favorable outcome. Here, we demonstrate that lysine specific demethylase 1 (LSD1) inhibition potentiates cytotoxic effect of KIT inhibition in KIT mutant AML. We identified loss of PU.1 binding to be a key feature of LSD1 inhibition, contributing to a decrease in MYC enhancer and promoter activation. This loss of MYC enhancer/promoter activation results in decreased MYC expression and binding at proliferation associated promoters decreasing cell cycle progression. Our results nominate PI3K/AKT pathway inactivation as a key feature of KIT and LSD1 inhibition ultimately leading to decreased MYC and blocking LSD1 from activating its targets. Our findings support a mechanistic model for synergy between dual KIT and LSD1 inhibition and suggest this combination should be investigated in a clinical setting.

2022-05-29 | GSE182150 | GEO

Analysis of miRNAs in MCF7 cells regulated by LSD1

Project description:Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates metastasis in luminal breast cancer. Thus, the characterization of miRNAs in MCF7 cells regulated by LSD1 is imperative in clarifying intercellular signaling.

2024-03-04 | GSE218200 | GEO

IP-MS of LSD1 and ER in treated Breast cancer cells

Project description:These proteomic data were produced in order to assess the effect of drug 3324, a pan-lysine demethylase inhibitor, on the estrogen receptor (ER) and Lysine Demethylase1 (LSD1)protein interaction networks.

2021-09-08 | PXD012781 | Pride

CUT & RUN analysis of H3K4me2 mark upon LSD1 inhibition

Project description:Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cancer cell survival, including in prostate cancer. LSD1 has been shown to perfrom catalytic independent function sto promote prostate cancer survival. Here, we tested the levels of LSD1's canonical target H3K4me2 upon LSD1 inhibition with SP2509 across the genome using CUT and RUN analysis.

2023-08-30 | GSE235211 | GEO

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