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针对DNMT3A介导的氧化酸化,以克服地幔细胞淋巴瘤中易布鲁替尼抗性

Nguyet-Minh Hoang¹, Yunxia Liu², Paul D Bates³

¹Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

Cell reports. Medicine

|March 30, 2024

概括

通过重编程新陈代谢,DNA甲基转移酶3A (DNMT3A) 驱动了地幔细胞淋巴瘤 (MCL) 中的易布鲁替尼抗性. 用desitabine针对DNMT3A提供了一种新的策略,以克服复发性/耐药性MCL的抗性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
生物化学生物化学

背景情况:

像ibrutinib这样的Bruton tyrosine kinase (BTK) 抑制剂在地幔细胞淋巴瘤 (MCL) 中有效.
对易布鲁替尼的获得性耐药性显著影响了MCL患者的长期存活率.
在MCL中依据ibrutinib耐药性的机制需要进一步阐明.

研究的目的:

为了研究DNA甲基转移酶3A (DNMT3A) 在调解MCL中的ibrutinib耐药性的作用.
探索针对DNMT3A在克服ibrutinib耐药性的治疗潜力.

主要方法:

在ibrutinib治疗的MCL细胞中分析DNMT3A表达.
对DNMT3A.的遗传和药理抑制.
研究DNMT3A与转录因子MEF2B和MYC的相互作用.
对氧化酸化 (OXPHOS) 的代谢重编程的评估.
在体外和体内使用患者衍生的异种移植模型中使用德西他的疗效研究.

主要成果:

DNMT3A的表达在耐易布鲁替尼的MCL细胞中被上调.
DNMT3A可以独立于其DNA甲基化活性来调解ibrutinib的耐药性.
DNMT3A与MEF2B和MYC相互作用,诱导MYC目标基因,促进OXPHOS.
低剂量德丁治疗在体外和体内抑制了耐易布鲁替尼的MCL细胞的生长.

结论:

通过代谢重编程,DNMT3A在MCL中的易布鲁替尼抗性中发挥着关键作用.
针对DNMT3A介导的OXPHOS重编程与decitabine是一个有前途的治疗策略复发性/难治性MCL.

关键词:

在DNMT3A中,它是DNMT3A.奥克斯福斯 (OXPHOS) 是一个基因调节基因调节基因调节耐药性耐药性耐药性耐药性耐药性地毯细胞淋巴瘤

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