Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA345242 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
Project description:We describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) are highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation-like phenotypic change from erythroid/megakaryocytic lineages into granulomonocytic lineage. Our findings provide the rationale for testing LSD1 inhibitors as potential treatments with a novel mechanism of action for AML, particularly AEL and AMKL.
2017-01-01 | GSE87580 | GEO
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
Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.
2023-03-11 | PXD030581 | Pride
Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To investigate the mechanism of LSD1 efficacy in SCLC cell lines we used chromatin immunoprecipitation (ChIP) sequencing studies to examine the genomic distribution of LSD1 as well as H3K4me2 and H3K4me1 in NCI-H526 SCLC cells in the absence and presence of LSD1 inhibition.
2015-07-14 | E-GEOD-66297 | biostudies-arrayexpress
Project description:The lysine-specific demethylase LSD1/KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). Inhibition of its expression or catalytic activity overcomes the differentiation block and reduces colony formation potential. We have developed ORY-1001 as highly potent and selective inhibitor of KDM1A. Treatment of AML cell lines with ORY-1001 induces accumulation of H3K4me2 marks at KDM1A target genes, compromises leukemic stem cell capacity, and provokes blast differentiation. ORY-1001 exhibits potent synergy with standard of care drugs and with inhibitors of other epigenetic targets; reduces tumor growth and extends survival in mouse xenograft models of acute leukemia. To develop tools for use in clinical trials, we selected a panel of surrogate biomarkers for pharmacodynamic analysis based on expression changes in a panel of 24 leukemia cell lines. ORY-1001/RG6016 was the first selective KDM1A inhibitor to enter the clinic and is currently being evaluated in leukemia and solid tumor clinical trials.
2018-08-19 | GSE94567 | GEO
Project description: Not available
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:C/EBPα induces highly efficient macrophage transdifferentiation of selected B-lymphoma /leukemia cell lines and impairs their tumorigenicity
| PRJNA192979 | ENA