B细胞急性淋巴细胞白血病和多发性髓瘤细胞系对MEN1的依赖性超出了MEN1-KMT2A相互作用的范围
Tatjana Magdalena Wolffhardt1, Franz Ketzer2, Stefano Telese1
1Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
International journal of molecular sciences
|November 25, 2023
概括
门蛋白 (MEN1) 对白血病至关重要,不仅仅是通过其与KMT2A的相互作用. 所有经过测试的B-ALL和大多数多发性骨髓瘤细胞系都依赖MEN1,这表明了更广泛的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 血液学 血液学 血液学
背景情况:
- 门 (MEN1) 是一种参与细胞增殖,基因转录,DNA修复和信号传导的支架蛋白.
- MEN1和KMT2A/MLL1 (MLLr) 融合蛋白之间的相互作用在某些血液性恶性瘤中至关重要,如MLLLr AML和B-ALL.
- 目前的疗法针对的是MEN1-KMT2A相互作用,但白血病中MEN1依赖的替代机制尚未探索.
研究的目的:
- 调查B细胞急性淋巴细胞白血病 (B-ALL) 和多发性髓瘤中MEN1依赖性是否仅与MEN1-KMT2A相互作用有关.
- 探索推动血液性恶性瘤中MEN1依赖的替代机制.
主要方法:
- 对B-ALL细胞系的公开可用的基因表达数据库的分析.
- 在各种B-ALL和多发性髓瘤细胞系中,shRNA介导的MEN1的敲击.
- 对MEN1枯竭的细胞系敏感性的评估,与驱动突变和MLLR状态相关联.
主要成果:
- 在B-ALL细胞系中MEN1依赖性与MLLR的存在没有相关性.
- 所有测试的B-ALL细胞系都对MEN1枯竭表现出敏感性,而不管它们的特定驱动突变.
- 大多数多发性骨髓瘤细胞系,即使是没有MLLR的细胞系,也对MEN1基因枯竭敏感.
结论:
- MEN1的致癌作用超出了在血液性恶性瘤中与KMT2A的相互作用.
- MEN1依赖是B-ALL和多发性骨髓瘤的一个共同特征,独立于MLLR.
- 向降解MEN1或开发诱导全球结构变化的结合剂可能提供比抑制单个蛋白相互作用更有效的治疗策略.
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