依赖ETV4的转录可塑性维持MYC表达,并导致多发性髓瘤中的IMID抵抗
Paola Neri1, Benjamin G Barwick2, David Jung1
1Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, -Canada.
Blood cancer discovery
|November 7, 2023
概括
一项新的研究显示,转录因子ETV4通过维持瘤基因表达来驱动多发性骨髓瘤中对免疫调节药物 (IMiDs) 的耐药性. 这一发现强调了转录性可塑性作为IMID耐药性的关键机制.
科学领域:
- 血液学 血液学 血液学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 免疫调节药物 (IMiDs) 在治疗多发性骨髓瘤 (MM) 中至关重要.
- 大多数患者对IMiDs产生耐药性,其潜在机制尚未完全理解.
- IMiD的有效性取决于IKZF1和IKZF3的降解,它们调节瘤基因表达.
研究的目的:
- 阐明多发性骨髓瘤IMiD耐药性的机制.
- 确定克服IMiD耐药性的新型治疗点.
主要方法:
- 染色体免疫沉测序 (ChIP-seq) 用于分析转录因子的结合.
- 通过CRISPR/Cas9基因编辑来消去ETV4.
- 在MM细胞系和患者数据中分析ETV4表达.
主要成果:
- IMiD治疗普遍消耗了与染色质结合的IKZF1.1.
- 从增强剂中驱逐P300和BRD4协激剂是IMID敏感细胞的特征.
- ETV4与IKZF1占用的增强剂结合,可以替代IKZF1的功能.
- 通过ETV4剥离,可以使IMiD耐药的MM细胞对IMiD产生敏感性.
- 高ETV4表达与IMID耐药性,不良预后和MM患者的复发相关.
结论:
- 由ETV4介导的转录因子冗余是MM中IMID耐药性的新机制.
- ETV4保持瘤原增强剂活性,减轻对IKZF1和IKZF3.3的依赖.
- 针对转录性可塑性提供了一种新的策略,以克服多发性骨髓瘤中的IMiD抵抗.
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