“The findings provide a paradigm shift in understanding how drug resistance develops,” said Jinghui Zhang, Ph.D., chair of the Department of Computational Biology at St. Jude Children’s Research Hospital. “The results also suggest potential treatment strategies for ALL patients who relapse, including screening to identify those who should avoid additional thiopurine treatment.”
Zhang is co-corresponding author of the study with Bin-Bing Zhou, Ph.D., of Shanghai Children’s Medical Center; and Renate Kirschner-Schwabe, MD, of Charite-Universitaetsmedizin Berlin.
The roots of relapse
While 94% of St. Jude patients with ALL survive for five years, relapse remains the leading cause of death for children and adolescents with ALL worldwide.
This study included ALL samples collected from relapsed pediatric ALL patients in the US, China and Germany. Researchers analyzed more than 1,000 samples collected at different times of the patients’ treatment, including samples from 181 patients collected at diagnosis, remission and relapse.
Co-first author Samuel Brady, Ph.D., of St. Jude Computational Biology, identified a mutational signature that helped decipher the process. Mutational signatures reflect the history of genetic changes in cells.
Brady and colleagues linked increased thiopurine-induced mutations to genes such as MSH2 that are mutated in leukemia. The mutations inactivated a DNA repair process called mismatch repair and made ALL resistant to thiopurines. The combination resulted in a 10-fold increase in ALL mutations, including an alteration in the tumor suppressor gene TP53. The mutation, TP53 R248Q, promoted resistance to multiple chemotherapy drugs, including vincristine, daunorubicin, and cytarabine.
Working in two cell lines in the lab, Zhou and his colleagues replicated the thiopurine-induced TP53 mutations and chemotherapy resistance. The study provided the first direct genomic and experimental evidence of chemotherapy-induced drug resistance. “This study not only changes our ALL treatment considerations, but also opens the door to mechanistically study how defective repair generates drug-resistant mutations,” Zhou said.
The role of chemotherapy in relapse
Researchers estimate that treatment-induced mutations play a role in 25% of pediatric ALL relapses. Eight percent of patients in this study had evidence of the thiopurine-associated mismatch repair signature.
“In the future, it may be possible to monitor the bone marrow during treatment as a way to detect these mutational signatures early enough to help identify at-risk patients who may be candidates for emerging therapies such as CAR-T cells,” Zhang said. But the researchers emphasized that the benefits of thiopurine treatment outweigh the risks, noting that most patients are not affected by thiopurine-induced mutations.
Authors and funding
The other first authors are Fan Yang, Chao Tang, Huiying Sun and Lijuan Du, all of the Shanghai Jiao Tong University School of Medicine. The other authors are Malwine Barz, Arend von Stackelberg and Cornelia Eckert of Charite-Universitaetsmedizin; Yao Chen, Houshun Fang, Xiaomeng Li, Jiaoyang Cai, Lixia Ding, Tianyi Wang, Shuhong Shen, Hongzhuan Chen, Caiwen Duan, Yu Liu, Hui Li and Benshang Li of the Shanghai Jiao Tong University School of Medicine, and Xiaotu Ma, Pandurang Kolekar, Omkar Pathak and Jeffery KLco of St. Jude.
The research was funded in part by the National Natural Science Foundation of China; China’s National Key R&D Program; Shanghai Rising-Star Program; German Childhood Cancer Foundation and ALSAC, the St. Jude fundraising and awareness organization.