Nat Cancer:化疗和错配修复缺陷协同促进TP53突变的发生和急性淋巴细胞白血病的复发

2021-07-24 xiaozeng MedSci原创

TP53是癌症中最常见的突变基因。

TP53是癌症中最常见的突变基因。体细胞TP53突变主要位于DNA结合结构域中,说明p53的转录活性在肿瘤的抑制作用中的重要性。

化疗是儿童急性淋巴细胞白血病(ALL)的标准治疗策略,但患者有时会出现疾病的复发以及耐药性的产生。既往研究显示,在儿童ALL中,TP53 突变在诊断时很少见,但在复发时富集且能够独立预测患者的不良结局。然而,复发时TP53突变富集的原因尚不清楚。

在该研究中,研究人员揭示了化疗诱导耐药相关突变导致疾病复发的特定机制。通过复发性ALL的基因组和功能分析显示,错配修复(MMR)缺陷型白血病中的硫嘌呤治疗可诱导TP53 R248Q突变(thio-dMMR)。

复发性ALL中的TP53突变

克隆进化分析揭示了一些ALL患者的连续MMR失活和TP53突变。研究人员发现,获得性TP53 R248Q突变与治疗中疾病的复发、患者较差的治疗反应和对多种化疗药物的耐药性相关,这些过程可以通过药理学p53再激活来逆转。

协同作用诱导的TP53突变获取模型

总而言之,该研究结果揭示,复发性ALL中的TP53 R248Q突变源于硫嘌呤治疗和MMR缺陷的协同作用,并提出了预防或治疗TP53突变所引起的疾病复发的策略。


原始出处:

Yang, F., Brady, S.W., Tang, C. et al. Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse. Nat Cancer (22 July 2021).

 

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    2021-07-25 zhishijing
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    2021-07-25 zblhy
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    2021-07-24 @gxl

    非常受用

    0

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    2021-07-24 qingzipost

    值得学习

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