平衡激活和抑制:COREST-p300对抗性控制在AML中的视网膜酸驱动的差异化
Mina M Tayari1, Helena Gomes Dos Santos1, Sadat Dokaneheifard1
1Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
双重抑制LSD1/CoREST与Corin和ATRA协同作用,以克服急性髓性白血病 (AML) 的抵抗. 这种组合通过重新激活视网膜酸信号通路来促进强大的骨髓分化和亡.
科学领域:
- 血液学 血液学 血液学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 分子生物学分子生物学
背景情况:
- 基因组脱甲基酶KDM1A (LSD1) 对于造血分化至关重要,但在血液恶性瘤中表达很高.
- 抑制LSD1是一种潜在的策略,可以增强急性髓性白血病 (AML) 中的视网膜酸 (RA) 敏感基因表达.
研究的目的:
- 研究LSD1和RAR/RXR异构体在AML中的相互作用.
- 为了评估Corin的疗效,一个双LSD1/CoREST抑制剂,与全转网红酸 (ATRA) 结合用于AML治疗.
主要方法:
- 在基因组位置研究了LSD1与RAR/RXR的相互作用.
- 通过单剂和组合疗法 (Corin + ATRA) 评估差异化和诱导亡.
- 分析了H3K4me3水平,COREST-RAR/RXR复合物的破坏,以及p300联合激活器的招募.
主要成果:
- 在AML中,LSD1限制了染色质的可访问性和转录性激活AML分化程序.
- 科林与ATRA相结合,可以协同诱导强大的骨髓分化和亡.
- 组合疗法破坏了CoREST-RAR/RXR复合体,增强了p300的招募,并将染色质转移到一个活跃的状态.
结论:
- CoREST和p300之间的功能对立是AML中RA信号的关键调节轴.
- 科林和ATRA重新使非APLAML细胞对RA诱导的分化敏感,为ATRA耐药白血病提供治疗策略.
关键词:
在HDAC的基础上,HDAC是一个LSD1一个LSD1急性髓性白血病 (AML) 是一种疾病.差异化疗法是一种差异化疗法.增强剂是一种增强剂.表观遗传调节 表观遗传调节基斯顿基因基因基因基因基因基因基因基因基因基因基因基因基因基因在P300上,P300是P300.更多相关视频
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