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鉴定对AML1/ETO阳性白血病的生长和存活至关重要的表观遗传修饰剂

Jesús Duque-Afonso¹, Pia Veratti^1,2, Usama-Ur Rehman¹

¹Department of Hematology/Oncology/Stem Cell Transplantation, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany.

International journal of cancer

|August 15, 2024

概括

研究人员确定了关键的表观遗传调节者,DNMT1和ATR,对于急性髓性白血病 (AML) 细胞生长至关重要. 这些目标表明,通过药理抑制,新的AML疗法具有前途.

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:

有染色体转移的急性髓性白血病 (AML) 的异常基因表达通常涉及表观遗传修饰器失调.
由 (8;21) 转位产生的AML1/ETO融合蛋白在AML中表观遗传抑制了目标基因.
了解AML1/ETO阳性AML细胞对表观遗传修饰剂的依赖性对于治疗开发至关重要.

研究的目的:

为了确定AML1/ETO阳性AML细胞的增殖和存活所必需的关键表观遗传修饰剂.
验证已识别的修饰剂,并评估它们作为治疗点的潜力.

主要方法:

利用shRNA库的屏幕来识别AML1/ETO阳性细胞系 (Kasumi-1,SKNO-1) 中常见的枯竭基因.
在U937细胞中使用全球转录学来分析AML1/ETO诱导后的基因表达变化.
在多个细胞系中从遗传和药理上验证识别的标 (DNMT1,ATR).
在AML患者中评估DNMT1抑制剂 (decitabine) 的体内作用.

主要成果:

在AML1/ETO阳性细胞系中通过shRNA选识别了41个常见的枯竭基因.
验证的DNMT1和ATR对于AML1/ETO阳性AML细胞增殖和生存至关重要.
在 AML 患者中观察到 vivo 骨髓母细胞分化,当他们接受了decitabine治疗时.
转录组分析显示AML1/ETO诱导后有973个差异表达的基因,其中PARP2,PRKCD和SMARCA4被确定为下调和在shRNA屏幕中.

结论:

公正的shRNA查和转录组学确定了AML1/ETO阳性AML中的关键驱动器表观遗传调节者.
DNMT1和ATR是经过验证的对药物抑制敏感的标.
针对DNMT1和ATR的小分子抑制剂在AML治疗中显示出有希望的临床前和临床疗效.

关键词:

这是一个ATRATRATRATR.在DNA甲基转移酶中.急性骨髓性白血病 (AML) 是一种急性骨髓性白血病.表观遗传疗法是一种表观遗传疗法.这是一个shRNA屏幕.

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