Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

ABSTRACT: Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric di-methylation of arginine residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in MLL-fusion AMLs. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of pathways either regulated by PRMT5 or known to be relevant for AML (e.g. intracellular signaling, splicing and transcription), we have identified a synthetic lethality between inhibition of LSD1, a lysine demethylase known to affect AML blast differentiation, and PRMT5. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we have generated a new set of dual compounds that inhibit both PRMT5 and LSD1. Mechanistically, we show that these dual compounds elicit transcriptional and post-transcriptional (splicing) defects that recapitulate the combination therapy. Last, we were able to solve the X-ray co-crystal structure of one of the designed inhibitors with LSD1, thus elucidating its binding mode and providing a structural basis for the rational design of further inhibitors. In summary, our findings identify a novel drug combination strategy for the treatment of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278623 | GEO | 2026/02/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genome-wide CRISPR-Cas9 screen identifies druggable synthetic lethality between LSD1 and MTORC1 in MLL-translocated AML

Project description:Lysine Specific Demethylase 1 (LSD1 or KDM1A) is one of a number of epigenetic regulators which have recently emerged as candidate therapeutic targets in acute myeloid leukaemia (AML). Pharmacological inhibitors of LSD1 such as the tranylcypromine derivatives have already commenced evaluation in early phase clinical trials; however like all acute leukaemia therapies, it is unlikely that these inhibitors are effective as single agents. Therefore, there is a strong rationale to identify proteins that collaborate with LSD1 to maintain the leukemic phenotype and could be targeted in combination with LSD1 for enhanced therapeutic benefit. Using a genome-wide CRISPR-Cas9 dropout screen in human THP1 cells, we identified multiple regulatory components of the amino acid sensing arm of mTORC1 signalling - RRAGA, MLST8, and LAMTOR2 – as synthetic lethalities with LSD1 inhibition. Genetic and/or pharmacologic inhibition of selected genes in combination with LSD1 inhibition showed significant anti-leukemic activity by inducing a more extensive and wide-ranging myeloid differentiation program and reducing cell proliferation in THP1 and primary human AML cells in vitro and in vivo. In conclusion, we report that inhibition of mTORC1 sensitizes human MLL-translocated AML cells to LSD1 inhibitor-mediated differentiation therefore highlighting a novel combination approach for evaluation in clinical trials.

2019-12-23 | GSE126486 | GEO

HMG20B stabilizes interaction of LSD1 with GFI1 on chromatin to confer 1 transcription repression and leukemia cell differentiation block

Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.

2023-03-11 | PXD030581 | Pride

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

A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

Project description:A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

| PRJNA1168104 | ENA

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 through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis.

2020-05-26 | PXD012954 | Pride

H3K4me2 profiling in C3H-10T1/2 preadipocytes [ChIP-seq]

Project description:By screening a collection of epigenetic compounds, we find that Lysine-Specific Demethylase 1 (LSD1) inhibitors repress brown adipocyte differentiation. RNAi-mediated Lsd1 knockdown shows similar effect, which can be rescued by expression of wild-type, but not catalytically inactive, LSD1. Furthermore, adenoviral Cre-mediated Lsd1 deletion in mice leads to inhibition of brown adipogenesis, validating the pivotal role of LSD1 in brown fat development in vivo. LSD1 represses gene expression by demethylating H3K4. To identify the target genes of LSD1 during BAT differentiation, we analyzed the H3K4me2 enrichment in preadipocyte.

2016-08-30 | GSE74901 | GEO

Interplay between CoREST, p300 and retinoic acid signaling in Acute myeloid leukemia [RNA-seq]

Project description:The histone demethylase KDM1A (LSD1), a component of the CoREST corepressor complex, is highly expressed in hematologic malignancies and regulates hematopoietic differentiation. Despite its essential developmental role, LSD1 inhibition has emerged as a promising strategy to enhance retinoic acid (RA)-responsive gene expression in subsets of acute myeloid leukemia (AML). Here, we show that LSD1 physically interacts with RAR/RXR heterodimers at specific genomic loci, restricting chromatin accessibility and transcriptional activation of differentiation programs. Single-agent inhibition of LSD1 or HDACs promotes only partial differentiation. In contrast, Corin, a dual LSD1/CoREST inhibitor, synergizes with all-trans retinoic acid (ATRA) to induce robust myeloid differentiation and apoptosis. Corin treatment increases H3K4me3 and H3K27ac at promoters of ATRA-responsive genes and disrupts CoREST–RAR/RXR complexes, enabling recruitment of the coactivator p300. This epigenetic switch facilitates transcriptional reprogramming essential for terminal differentiation. Our findings identify the functional antagonism between CoREST and p300 as a regulatory axis of RA signaling in AML. Targeting this mechanism with Corin and ATRA re-sensitizes non-APL AML cells to RA-induced differentiation, suggesting a broader therapeutic approach for overcoming resistance in ATRA-refractory leukemias.

2026-02-20 | GSE300988 | GEO

Interplay between CoREST, p300 and retinoic acid signaling in Acute myeloid leukemia [ATAC-seq]

2026-02-20 | GSE300987 | GEO

Interplay between CoREST, p300 and retinoic acid signaling in Acute myeloid leukemia [ChIP-seq]

2026-02-20 | GSE300986 | GEO