Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse.
Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse.
复制标题
化疗和错配修复缺陷共同促进 TP53 突变和 ALL 复发。
DOI：
10.1038/s43018-021-00230-8
复制
发表时间：
2021
期刊：
影响因子：
22.7
通讯作者：
Hong
中科院分区：
文献类型：
--
作者：
Fan Yang;Samuel W. Brady;Chao Tang;Huiying Sun;Lijuan Du;Malwine J. Barz;Xiaotu Ma;Yao Chen;Houshun Fang;Xiaomeng Li;P;urang Kolekar;Omkar Pathak;Jiaoyang Cai;Lixia Ding;Tianyi Wang;Arend von Stackelberg;Shuhong Shen;Cornelia Eckert;Jeffery M. Klco;Hong
化疗是儿科急性淋巴细胞白血病（ALL）的标准治疗方法，有时会复发并伴有化疗耐药特征。然而，复发性ALL中获得性耐药突变是否预先存在或由治疗诱导仍然未知。在这里，我们提供了化疗诱导耐药相关突变导致复发的特定机制的直接证据。使用复发ALL的基因组和功能分析，我们表明，硫嘌呤治疗错配修复（MMR）缺陷型白血病诱导热点TP53 R248Q突变通过一个特定的突变签名（硫代dMMR）。克隆进化分析显示，在一些ALL患者中，MMR失活后出现TP53突变。获得性TP53 R248Q突变与治疗中复发、治疗反应差和对多种化疗药物的耐药性相关，这可以通过药理学p53再激活来逆转。我们的研究结果表明，TP53 R248Q在复发的ALL起源于通过协同突变的巯基嘌呤治疗和MMR缺陷，并提出了预防或治疗TP53突变复发的策略。
Chemotherapy is a standard treatment for pediatric acute lymphoblastic leukemia (ALL), which sometimes relapses with chemoresistant features. However, whether acquired drug-resistance mutations in relapsed ALL pre-exist or are induced by treatment remains unknown. Here we provide direct evidence of a specific mechanism by which chemotherapy induces drug-resistance-associated mutations leading to relapse. Using genomic and functional analysis of relapsed ALL we show that thiopurine treatment in mismatch repair (MMR)-deficient leukemias induces hotspot TP53 R248Q mutations through a specific mutational signature (thio-dMMR). Clonal evolution analysis reveals sequential MMR inactivation followed by TP53 mutation in some patients with ALL. Acquired TP53 R248Q mutations are associated with on-treatment relapse, poor treatment response and resistance to multiple chemotherapeutic agents, which could be reversed by pharmacological p53 reactivation. Our findings indicate that TP53 R248Q in relapsed ALL originates through synergistic mutagenesis from thiopurine treatment and MMR deficiency and suggest strategies to prevent or treat TP53-mutant relapse.