As early as 2014, the Affiliated Children’s Medical Center and the St.
Sud Children’s Research Hospital in the United States initiated the Chinese Pediatric Oncology Committee’s Emergency and Lymphatic Multi-Center Collaborative Group Program (CCCG-ALL-2015).
The results showed that the 5-year overall survival rate was 91.
The event survival rate was 80.
3%, and the curative effect reached the international advanced level
However, it is not clear how leukemia cells acquire drug-resistant gene mutations
At present, there are two mainstream views: 1.
The drug-resistant gene mutations already exist in the form of tiny clones when cancer occurs, and they are enriched by drug screening during the chemotherapy process; 2.
The drug-resistant gene mutations do not exist at the time of cancer.
It is regained in the course of treatment
Among them, whether chemotherapy can directly induce drug-resistant mutations has been lack of relevant experimental evidence
July 22, 2021, National Children's Medical Center (Shanghai)/Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Zhou Binbing, Key Laboratory of Children's Hematological Tumors, National Health Commission The team, the Jinghui Zhang team of the St.
Sude Children’s Research Hospital in the United States, and the Renate Kirschner-Schwabe team of the Charles University Hospital in Germany have published an online publication titled "Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse" in the international authoritative journal Nature Cancer.
"The latest research results (https://doi.
This study provides the first direct genomics and cytology experimental evidence for ALL chemotherapy drugs to induce drug-resistant mutations, indicating that the chemotherapeutic drug mercaptopurine may directly induce drug-resistant gene mutations in patients with mismatch repair defects, making tumor cells resistant to a variety of Resistance to other chemotherapeutic drugs has led to the recurrence of leukemia
The study comprehensively analyzed samples of 1951 ALL patients from China, the United States, and Germany, and found that the tumor suppressor gene TP53 R248Q mutation was significantly enriched in relapsed ALL
This mutation will cause ALL cells to be resistant to multiple chemotherapeutic drugs, such as vincristine, daunorubicin, cytarabine and methotrexate
At the same time, the study used whole-genome sequencing to analyze paired samples from 181 childhood ALL patients with initial, remission and recurrence, and found for the first time the characteristic mercaptopurine mutation signature of relapsed ALL, which reflects the genetics of mercaptopurine-induced gene mutations during chemotherapy.
The course of change
Further studies have found that mismatch repair defects significantly increase the rate of gene mutations induced by mercaptopurine, such as the tumor suppressor gene TP53 R248Q mutation
The study further reproduced the process of mercaptopurine directly inducing TP53 mutation and chemotherapy resistance in in vitro cell line experiments
The results of this study provide experimental evidence that chemotherapeutics may directly induce drug-resistant mutations
At the same time, it suggests that ALL patients with mismatch repair defects (about 8% of relapsed patients) will face a huge risk of mercaptopurine medication, and the treatment strategy should be changed
The research results suggest that in the future, monitoring the bone marrow during the treatment process, detecting related mutations as soon as possible to guide clinical medication, and screening high-risk patients who may be the beneficiaries of emerging therapies such as CAR-T are of positive significance for improving the accuracy of leukemia treatment
This work also has an important contribution to the clonal evolution mechanism of leukemia.
It was found that some drug-resistant mutations were not pre-existed in small amounts at the initial onset, but were directly induced by chemotherapeutic drugs, which changed people's understanding and cognition of the source of drug-resistant mutations