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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300988 | GEO | 2026/02/20

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE300988_GEO_rnaseq_raw_counts_ATRA_Corin_hg38_genes.txt.gz	Txt
	GSE300988_RAW.tar	Raw
	GSE300988_RNAseq_ATRA_Corin_vs_cntrl_SKNO1_gene_deseq2_out.txt.gz	Txt
	GSE300988_RNAseq_ATRA_Corin_vs_cntrl_U937_gene_deseq2_out.txt.gz	Txt

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Interplay between CoREST, p300 and retinoic acid signaling in Acute myeloid leukemia [CUT&Run]

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 | GSE300989 | GEO

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

2026-02-20 | GSE300986 | GEO

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

2026-02-20 | GSE300987 | 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 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

PML-RARa/RXR alters the epigenetic landscape in Acute Promyelocytic Leukemia

Project description:Many different molecular mechanisms have been suggested to be associated with PML-RAR dependent transformation of haematopoietic progenitors. Here, we investigated the role of PML-RAR and RXR in the organization of epigenetic structures at a genome-wide level. We identified 2722 high confidence PML-RAR binding sites in the leukemic model cell line NB4 and found PML-RAR colocalization with RXR to the vast majority of these binding regions. Importantly, these results could be corroborated and extended in primary blast cells of two APL patients. Through genome-wide epigenetic studies we show that treatment with pharmacological doses of all-trans retinoic acid ATRA induces global alterations in active H3 acetylation and repressive H3K27me3, H3K9me3 and DNA methylation chromatin modifications. However at the PML-RAR/RXR binding sites, ATRA only induces changes in H3 acetylation. These H3 acetylation alterations triggered by the loss of PML-RAR/RXR binding affect H3 acetylation and RNA polymerase II occupancy at nearby genes. Our results suggest that PML-RAR/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for haematopoietic differentiation, RAR signaling and epigenetic control is crucial to the transforming potential of PML-RAR/RXR. Examination of PML, RARa and RXR binding sites in leukemic cells before and after ATRA treatment, association with transcription via RNAPII occupancy and with chromatin modifications.

2009-12-17 | E-GEOD-18886 | biostudies-arrayexpress

PML-RARa/RXR alters the epigenetic landscape in Acute Promyelocytic Leukemia

2009-12-17 | GSE18886 | GEO

The CoREST complex inhibitor, corin, leads to decreased tumor growth, increased cellular differentiation and extended lifespan in atypical teratoid rhabdoid tumor xenograft models [RNA-seq]

Project description:Background. Atypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor in infants, and more than 60% of children with ATRT die from their tumor. ATRT is associated with mutational inactivation/deletion of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, suggesting that epigenetic events play a critical role in tumor development and progression. Moreover, disruption of SWI/SNF allows unopposed activity of epigenetic repressors, which contribute to tumorigenicity. We therefore explored the role of the CoREST repressor complex in ATRT. Methods. We evaluated the effects of the bifunctional LSD1/HDAC1/2 small molecule CoREST inhibitor, corin, on ATRT tumor cell growth, apoptosis, differentiation, gene expression and chromatin accessibility. Results. We found that corin inhibited the growth of ATRT cells regardless of their epigenetic subgroup, and was associated with increased tumor cell apoptosis and differentiation. ATAC-seq showed increases in chromatin accessibility in corin-treated ATRT cells, with changes seen at genes associated with neuronal differentiation and synaptic function. RNA-seq confirmed increased expression of neuronal differentiation genes and decreased DNA replication/cell cycle-associated genes in ATRT cells treated with corin. Corin suppressed orthotopic ATRT tumor growth, leading to significant extension of lifespan. In addition, increased histone acetylation (H3K9ac, H3K27ac) and methylation (H3K4Me1) was seen in corin-treated ATRT orthotopic xenografts, consistent with on-target pharmacodynamics. Conclusion. The CoREST inhibitor, corin, suppresses tumor growth, induces differentiation, and promotes apoptosis in ATRT, leading to significantly increased survival of mice bearing ATRT orthotopic xenografts. Our results suggest a potential application of CoREST complex inhibitors in patients with ATRT.

2025-03-27 | GSE285637 | GEO

The CoREST complex inhibitor, corin, leads to decreased tumor growth, increased cellular differentiation and extended lifespan in atypical teratoid rhabdoid tumor xenograft models [ATAC-seq]

2025-03-27 | GSE285636 | GEO

Targeting the scaffolding role of LSD1(KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation [RNA-seq]

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.

2020-04-20 | GSE128529 | GEO

Targeting the scaffolding role of LSD1(KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation [ChIP-seq]

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.

2020-04-20 | GSE128528 | GEO

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