Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse

DNA修复 化疗 癌症研究 DNA错配修复 突变 内科学 生物 突变 医学 遗传学 基因
作者
Fan Yang,Samuel W. Brady,Chao Tang,Huiying Sun,Lijuan Du,Malwine Barz,Xiaotu Ma,Yao Chen,Houshun Fang,Xiaomeng Li,Pandurang Kolekar,Omkar Pathak,Jiaoyang Cai,Lixia Ding,Tianyi Wang,Arend von Stackelberg,Shuhong Shen,Cornelia Eckert,Jeffery M. Klco,Hongzhuan Chen,Cai‐Wen Duan,Yu Liu,Hui Li,Benshang Li,Renate Kirschner‐Schwabe,Jinghui Zhang,Bin‐Bing S. Zhou
出处
期刊:Nature cancer [Springer Nature]
卷期号:2 (8): 819-834 被引量:34
标识
DOI:10.1038/s43018-021-00230-8
摘要

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. Zhou and colleagues demonstrate that thiopurine chemotherapy in mismatch repair-deficient ALL cells leads to R248Q TP53 mutations and clonal selection that favors on-treatment ALL relapse and chemoresistance.
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