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MEN1突变调解了临床耐敏抑制的发生

Florian Perner^1,2, Eytan M Stein³, Daniela V Wenge¹

¹Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

|March 16, 2023

概括

在某些白血病的治疗中, 然而,通过MEN1基因的突变,获得的耐药性可能会发展,从而使癌细胞通过保持menin和MLL1在染色质上逃避治疗.

科学领域:

血液学
分子生物学
癌症研究

背景情况:

染色体结合蛋白调节细胞状态,特别是在造血过程中.
涉及KMT2A重组或NPM1突变的白血病取决于白血病基因表达的menin蛋白.
门抑制剂,如revumenib,通过破坏门-MLL1相互作用,在这些白血病中显示出临床疗效.

研究的目的:

研究KMT2Ar和NPM1突变白血病中获得的抗敏抑制剂的机制.
鉴定产生针对性治疗耐药性的基因变异.
了解耐药性突变如何影响药物向相互作用和染色质占用.

主要方法:

来自对revumenib获得耐药性的患者的MEN1基因体突变的分析.
在异种移植模型中验证抗性机制.
使用一个公正的基编辑器屏幕来识别抵抗突变.
突变的脑蛋白和它们与revumenib和MLL1的相互作用的生物化学和结构分析.

主要成果:

在耐药患者样本中,在revumenib-menin界面上发现了MEN1的体质突变.
这些突变在临床前模型中保持不变,并通过无偏见的查确定.
突变导致结构变化,降低了revumenib的结合,但保留了 menin- MLL1的相互作用.
耐药突变物阻止药物诱导的menin和MLL1从染色体中排离.

结论:

获得的抗敏抑制剂是由药物结合界面的特定MEN1突变驱动的.
这些突变代表了KMT2Ar和NPM1突变白血病的保护性抵抗机制.
这项研究表明治疗选择压力驱动抗性突变,导致长时间的染色体占用,这是染色体向药物的潜在常见抗性机制.

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