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

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. Overall design: AML cell lines were treated with ATRA and Corin or DMSO (vehicle control), followed by ChIP-seq, ATAC-seq, RNA-seq, and CUT&RUN to assess transcriptional and epigenomic changes.

组蛋白去甲基化酶KDM1A（LSD1）是CoREST共抑制复合物的组成成分，在血液系统恶性肿瘤中高表达并调控造血分化。尽管其在发育过程中发挥关键作用，LSD1抑制已成为在部分急性髓系白血病（AML）中增强视黄酸（RA）应答基因表达的潜在策略。本研究发现，LSD1可在特定基因组位点与视黄酸受体/类视黄醇X受体（RAR/RXR）异二聚体发生物理互作，进而限制染色质可及性与分化程序的转录激活。单独抑制LSD1或组蛋白去乙酰化酶（HDACs）仅能诱导部分分化。与之相反，双靶点LSD1/CoREST抑制剂Corin可与全反式视黄酸（ATRA）协同，诱导强效髓系分化与细胞凋亡。Corin处理可提升ATRA应答基因启动子区域的H3K4三甲基化（H3K4me3）与H3K27乙酰化（H3K27ac）水平，并破坏CoREST-RAR/RXR复合物，促进共激活因子p300的招募。该表观遗传开关可促进终末分化所需的转录重编程。本研究揭示CoREST与p300之间的功能拮抗是AML中RA信号通路的调控轴。通过Corin与ATRA靶向该机制，可使非急性早幼粒细胞白血病（APL）的AML细胞重新对RA诱导的分化敏感，这为克服ATRA难治性白血病的耐药性提供了更广泛的治疗策略。实验整体设计：将AML细胞系用ATRA、Corin或二甲基亚砜（DMSO，溶剂对照）处理，随后通过染色质免疫共沉淀测序（ChIP-seq）、转座酶可及性测序（ATAC-seq）、RNA测序（RNA-seq）及切割与释放测序（CUT&RUN）评估转录与表观基因组变化。