Back to Search Start Over

Nascent transcript and single-cell RNA-seq analysis defines the mechanism of action of the LSD1 inhibitor INCB059872 in myeloid leukemia.

Authors :
Johnston, Gretchen
Ramsey, Haley E.
Liu, Qi
Wang, Jing
Stengel, Kristy R.
Sampathi, Shilpa
Acharya, Pankaj
Arrate, Maria
Stubbs, Matthew C.
Burn, Timothy
Savona, Michael R.
Hiebert, Scott W.
Source :
Gene. Aug2020, Vol. 752, pN.PAG-N.PAG. 1p.
Publication Year :
2020

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
03781119
Volume :
752
Database :
Academic Search Index
Journal :
Gene
Publication Type :
Academic Journal
Accession number :
143573941
Full Text :
https://doi.org/10.1016/j.gene.2020.144758