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LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164560 | GEO | 2021/12/01

REPOSITORIES: GEO

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LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [RNA-seq]

Project description:The histone de-methylase LSD1 is over-expressed in different haematological tumours, like AML, where it sustains carcinogenesis by promoting the clonogenic potential of leukemic stem cells. Emerging as a promising epigenetic target for the treatment of these tumour types, various LSD1 inhibitors have been developed in the last years, despite their mechanism of action in cancer cells is often not fully clarified. In this study, we characterized a novel mode of action of the inhibitors MC2580 and DDP-38003 and demonstrated that they trigger myeloid differentiation of AML by down-regulating GSE1 protein, a LSD1 interactor on chromatin. By studying the phenotypic effects of GSE1 depletion in NB4 cells, we observed a strong decrease of cell proliferation in vitro, and of tumour growth in vivo. Comparing the transcriptomic changes induced by GSE1 knock-down with those elicited by LSD1 pharmacological inhibition, we found a common set of genes up-regulated and linked with immune response and cytokine-mediated signalling. Mechanistically, we found that several promoters of these genes are bound by both LSD1 and GSE1 at basal state and that GSE1 binding is strongly reduced upon LSD1 inhibition, as a consequence of its reduced expression. By describing for the first time that LSD1-GSE1 interaction on chromatin enforces the silencing of genes linked to myeloid differentiation and by highlighting that this interaction can be overcome by LSD1 inhibitors, our study offers a new perspective on the use of these compounds to trigger differentiation in leukaemia through GSE1 modulation.

2021-12-01 | GSE164559 | GEO

LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [ChIP-seq]

2021-12-01 | GSE164553 | GEO

LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin

Project description:LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin

| PRJNA691206 | ENA

LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [RNA-seq]

Project description:LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [RNA-seq]

| PRJNA691208 | ENA

LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [ChIP-seq]

Project description:LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [ChIP-seq]

| PRJNA691202 | ENA

Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-03-27 | GSE63222 | GEO

Targeting the scaffolding role of LSD1(KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-20 | GSE128530 | GEO

Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML.

Project description: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.

| S-EPMC8830420 | biostudies-literature

HMG20B stabilizes interaction of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-06 | GSE192975 | GEO

Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation.

Project description:The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

| S-EPMC7141832 | biostudies-literature

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