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Updated: Oct 11, 2025
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML
Luciano Nicosia1,2, Francesca Ludovica Boffo1, Elena Ceccacci1
1Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, 20139, Italy.
Abstract:
The histone demethylase LSD1 is over-expressed in hematological tumors and has emerged as a promising target for anticancer treatment, so that several LSD1 inhibitors are under development and testing, in preclinical and clinical settings. However, the complete understanding of their complex mechanism of action is still unreached. Here, we unraveled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the downregulation of the chromatin protein GSE1. Analysis of the phenotypic effects of GSE1 depletion in NB4 cells showed a strong decrease of cell viability in vitro and of tumor growth in vivo. Mechanistically, we found that a set of genes associated with immune response and cytokine-signaling pathways are upregulated by LSD1 inhibitors through GSE1-protein reduction and that LSD1 and GSE1 colocalize at promoters of a subset of these genes at the basal state, enforcing their transcriptional silencing. Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights into GSE1 as a novel therapeutic target for AML.
Insights
LSD1 inhibitors induce acute myeloid leukemia (AML) cell differentiation by downregulating GSE1, a chromatin protein. This novel mechanism reveals GSE1 as a potential therapeutic target for AML treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Histone demethylase Lysine Specific Demethylase 1 (LSD1) is overexpressed in hematological tumors.
- LSD1 inhibitors are under development as anticancer agents, but their mechanisms of action require further elucidation.
Purpose of the Study:
- To investigate the novel mechanism of action of LSD1 inhibitors MC2580 and DDP-38003 in acute myeloid leukemia (AML).
- To explore the role of chromatin protein GSE1 in LSD1 inhibitor-induced AML cell differentiation.
Main Methods:
- Analysis of phenotypic effects of GSE1 depletion in NB4 cells (AML cell line).
- Assessment of cell viability in vitro and tumor growth in vivo.
- Investigation of gene expression changes related to immune response and cytokine signaling.
- Chromatin immunoprecipitation to determine protein localization at gene promoters.
Main Results:
- LSD1 inhibitors MC2580 and DDP-38003 induce AML cell differentiation via downregulation of GSE1.
- GSE1 depletion significantly reduces cell viability and tumor growth.
- LSD1 inhibitors upregulate immune response and cytokine-signaling genes by reducing GSE1.
- LSD1 and GSE1 colocalize at silenced gene promoters, and inhibitors reduce GSE1 binding, activating differentiation programs.
Conclusions:
- LSD1 inhibitors exert their anticancer effects through a novel mechanism involving GSE1 downregulation and subsequent activation of myeloid differentiation pathways.
- GSE1 represents a promising new therapeutic target for AML treatment.
