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.
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.
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.
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.
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.
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.
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.