Nascent transcript and single-cell RNA-seq analysis defines the mechanism of action of the LSD1 inhibitor INCB059872 in myeloid leukemia
| Autor: | Gretchen Johnston, Scott W. Hiebert, Michael R. Savona, Jing Wang, Matthew C. Stubbs, Pankaj Acharya, Qi Liu, Timothy Burn, Maria Pia Arrate, Haley E. Ramsey, Shilpa Sampathi, Kristy R. Stengel |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Myeloid THP-1 Cells Azacitidine Antineoplastic Agents Biology Article 03 medical and health sciences Mice 0302 clinical medicine Megakaryocyte Cell Line Tumor Gene expression Exome Sequencing Genetics medicine Animals Humans RNA-Seq Progenitor cell Histone Demethylases Gene Expression Regulation Leukemic Stem Cells Myeloid leukemia Cell Differentiation General Medicine DNA-Binding Proteins Mice Inbred C57BL Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Female Bone marrow Stem cell Single-Cell Analysis medicine.drug Transcription Factors |
| Zdroj: | Gene |
| ISSN: | 1879-0038 |
| Popis: | Drugs targeting chromatin-modifying enzymes have entered clinical trials for myeloid malignancies, including INCB059872, a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1). While initial studies of LSD1 inhibitors suggested these compounds may be used to induce differentiation of acute myeloid leukemia (AML), the mechanisms underlying this effect and dose-limiting toxicities are not well understood. Here, we used precision nuclear run-on sequencing (PRO-seq) and ChIP-seq in AML cell lines to probe for the earliest regulatory events associated with INCB059872 treatment. The changes in nascent transcription could be traced back to a loss of CoREST activity and activation of GFI1-regulated genes. INCB059872 is in phase I clinical trials, and we evaluated a pre-treatment bone marrow sample of a patient who showed a clinical response to INCB059872 while being treated with azacitidine. We used single-cell RNA-sequencing (scRNA-seq) to show that INCB059872 caused a shift in gene expression that was again associated with GFI1/GFI1B regulation. Finally, we treated mice with INCB059872 and performed scRNA-seq of lineage-negative bone marrow cells, which showed that INCB059872 triggered accumulation of megakaryocyte early progenitor cells with gene expression hallmarks of stem cells. Accumulation of these stem/progenitor cells may contribute to the thrombocytopenia observed in patients treated with LSD1 inhibitors. |
| Databáze: | OpenAIRE |
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