Inhibition of LSD1 as a Therapeutic Strategy for Acute Myeloid Leukemia
Johnston, Gretchen Dawn
0000-0001-5626-1689
:
2020-07-20
Abstract
Chromatin-modifying enzymes have been identified as promising therapeutic targets for a variety of malignancies. One such target is the histone demethylase Lysine-Specific Demethylase 1 (LSD1), which is found in transcriptional repressor complexes and can remove mono- and di-methylation from H3K4. ln certain cases of acute myeloid leukemia (AML), LSD1 inhibition can induce differentiation of leukemic blasts into more mature myeloid cells. INCB059872 is a selective irreversible inhibitor of LSD1 that is in phase I clinical trials. Here, ChlP-seq and precision nuclear run-on sequencing (PRO-seq) were used to assess the earliest regulatory events associated with INCB059872 treatment in AML cell lines. Surprisingly, changes in histone acetylation and transcription preceded changes in histone methylation. The changes in nascent transcription could be traced back to a loss of CoREST activity and activation of GFl1-regulated genes, as INCB059872 disrupted the LSD1:GFl1 interaction. Additionally, single-cell RNA-seq analysis revealed that INCB059872 treatment in mice triggered accumulation of megakaryocyte early progenitor cells, which could explain the treatment-related thrombocytopenia observed with LSD1 inhibitors.