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RNA-seq of murine megakaryocyte progenitor cells treated with LSD1 inhibitor INCB059872

ABSTRACT: RNA-seq of murine megakaryocyte progenitor cells treated with LSD1 inhibitor INCB059872

PROVIDER: PRJNA606326 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11075224_1.fastq.gz	Fastqsanger.gz
	SRR11075224_2.fastq.gz	Fastqsanger.gz
	SRR11075225_1.fastq.gz	Fastqsanger.gz
	SRR11075225_2.fastq.gz	Fastqsanger.gz
	SRR11075226_1.fastq.gz	Fastqsanger.gz

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RNA-seq of murine megakaryocyte progenitor 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. We identified a population of cells within murine lineage-negative bone marrow that is expanded after treatment with INCB059872. Here we sorted cells from this population (Lin- Cd41+ Cd200r3-) and performed RNA-seq to measure gene expression changes caused by INCB059872. Consistent with the thrombocytopenia observed in LSD1i-treated mice, INCB059872 reduced expression of genes associated with platelet function.

2020-05-28 | GSE145211 | GEO

Single-cell RNA-seq: INCB059872 in wild-type murine bone marrow

Project description:INCB059872 is a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1) that is in phase 1 clinical trials in hematopoietic malignancies. Mice treated with INCB059872 had reduced platelet counts within 4 days of treatment. Here, we used single-cell RNA-seq to study the effects of INCB059872 on hematopoietic progenitor populations within wild-type murine bone marrow. Our results showed that INCB059872 triggered accumulation of megakaryocyte early progenitor cells with gene expression hallmarks of stem cells, which may begin to explain the thrombocytopenia observed in patients treated with LSD1 inhibitors.

2020-05-28 | GSE145279 | GEO

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

PRO-seq of 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. We used precision nuclear run-on sequencing (PRO-seq) to define early transcriptional changes associated with INCB059872 treatment. Changes in nascent transcription could be traced back to a loss of CoREST activity resulting in activation of GFI1-regulated targets.

2020-05-28 | GSE145071 | GEO

ChIP-seq for histone acetylation and methylation in 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. We performed ChIP-seq for histone modifications to define the earliest regulatory events associated with INCB059872 treatment. Changes in acetylation were more dramatic than changes in methylation, and these changes could be traced back to a loss of CoREST activity at GFI1-regulated targets.

2020-05-28 | GSE145166 | GEO

PRO-seq of THP-1 cells treated with LSD1 inhibitor INCB059872

Project description:PRO-seq of THP-1 cells treated with LSD1 inhibitor INCB059872

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GFI1B and LSD1 repress myeloid traits during megakaryocyte differentiation

Project description:Mutations in transcription factor Growth Factor Independence 1B (GFI1B) cause inherited bleedings with varying intensity possibly caused by different effects on the transcriptional function of GFI1B. We studied transcriptomic changes of normal and GFI1BT174N,H181Y,R184P,Q287* mutants in megakaryoblast MEG01 cells using RNA-sequencing. Compared to normal GFI1B each variant affected different gene modules with limited overlap between variants. Remarkably, GFI1BQ287* specifically activated a myeloid-associated gene module. Based on this finding we studied megakaryocyte differentiation using normal and GFI1BQ287* patient-derived induced pluripotent stem cells (IPSC) followed by single cell RNA-sequencing. This revealed a 45-fold decrease in the megakaryocyte/myeloid cell ratio in the GFI1BQ287* versus control condition. Moreover, myeloid specific genes were expressed within GFI1BQ287* but not normal megakaryocytes. Finally, we studied how megakaryocyte development was affected by inhibiting binding of GFI1B to Lysine Specific Demethylase 1 (LSD1), an interaction required for megakaryocyte development. Treatment of both MEG01 cells and normal IPSC-derived developing megakaryocytes with the small-molecule inhibitor GSK-LSD1 resulted in profound activation of myeloid gene programs within megakaryocytes, while the IPSC-derived megakaryocyte/myeloid ratio dropped two-fold. We conclude that GFI1B and LSD1 suppress myeloid differentiation allowing for proper megakaryocyte development. LSD1 inhibitor and GFI1BQ287*-mediated perturbation of this function causes myeloid skewing during megakaryocyte development.

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GFI1B and LSD1 repress myeloid traits during megakaryocyte differentiation

Project description:The transcription factor Growth Factor Independence 1B (GFI1B) recruits Lysine Specific Demethylase 1A (LSD1/KDM1A) to stimulate gene programs relevant for megakaryocyte and platelet biology. Inherited pathogenic GFI1B variants result in thrombocytopenia and bleeding propensities with varying intensity. Whether these affect similar gene programs is unknow. Here we studied transcriptomic effects of four patient-derived GFI1B variants (GFI1BT174N,H181Y,R184P,Q287*) in MEG01 megakaryoblasts. Compared to normal GFI1B, each variant affected different gene programs with GFI1BQ287* uniquely failing to repress myeloid traits. In line with this, single cell RNA-sequencing of induced pluripotent stem cell (iPSC)-derived megakaryocytes revealed a 4.5-fold decrease in the megakaryocyte/myeloid cell ratio in GFI1BQ287* versus normal conditions. Inhibiting the GFI1B-LSD1 interaction with small molecule GSK-LSD1 resulted in activation of myeloid genes in normal iPSC-derived megakaryocytes similar as observed for GFI1BQ287* iPSC-derived megakaryocytes. Thus, GFI1B and LSD1 facilitate gene programs relevant for megakaryopoiesis while simultaneously repressing programs that induce myeloid differentiation.

2024-03-28 | PXD050401 | Pride

Single-cell RNA-seq of AML patient bone marrow treated with INCB059872, azacitidine, or combination

Project description:INCB059872 is a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1) that is in phase 1 clinical trials in hematopoietic malignancies. We evaluated a pre-treatment bone marrow sample of a patient who showed a clinical response to INCB059872 + azacitidine treatment. Single-cell RNA-sequencing (scRNA-seq) showed that INCB059872 caused a shift in gene expression that was associated with GFI1/GFI1B regulation.

2020-05-28 | GSE145410 | GEO

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

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

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