Chemotherapy has helped make acute lymphoblastic leukemia (ALL) one of the most survivable childhood cancers. Now, a research team has shown how thiopurines may lead to mutations that set patients up for disease relapse. These findings were published by Yang et al in Nature Cancer.
The research provides the first direct genomic and experimental evidence in pediatric cancer that drug-resistant mutations can be induced by chemotherapy and are not always present at diagnosis.
Jinghui Zhang, PhD
“The findings offer a paradigm shift in understanding how drug resistance develops,” said co–corresponding author Jinghui Zhang, PhD, Chair of the Department of Computational Biology at St. Jude Children’s Research Hospital. “The results also suggest possible treatment strategies for patients with ALL who relapse, including screening to identify those who should avoid additional thiopurine treatment.”
Study Details
This study involved ALL samples collected from pediatric patients with relapsed disease in the United States, China, and Germany. Researchers analyzed more than 1,000 samples collected from the patients at different times in treatment, including samples from 181 patients collected at diagnosis, remission, and relapse.
Co–first author Samuel Brady, PhD, also of St. Jude’s Department of Computational Biology, identified a mutational signature that helped decipher the process. Mutational signatures reflect the history of genetic changes in cells.
Dr. Brady and his colleagues linked increased thiopurine-induced mutations to genes such as MSH2 that become mutated in leukemia. The mutations inactivated a DNA repair process called mismatch repair and rendered ALL resistant to thiopurines. The combination fueled 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 laboratory, researchers replicated the thiopurine-induced TP53 mutations and chemotherapy resistance. The research provided the first direct genomic and experimental evidence of chemotherapy-induced drug resistance mutations.
KEY POINTS
- The researchers linked increased thiopurine-induced mutations to genes such as MSH2 that become mutated in leukemia.
- The mutations inactivated the DNA mismatch-repair process and rendered ALL resistant to thiopurines.
- The combination fueled a 10-fold increase in ALL mutations, including an alteration in TP53. The mutation, TP53 R248Q, promoted resistance to multiple chemotherapy drugs, including vincristine, daunorubicin, and cytarabine.
“This study not only changes our ALL treatment considerations, but also opens the door to study mechanistically how defective repair generates drug-resistant mutations,” the authors added.
Chemotherapy’s Role in Relapse
Researchers estimate that treatment-induced mutations play a role in 25% of pediatric ALL relapse. 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 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 chimeric antigen receptor T-cell treatment],” Dr. Zhang said.
However, the researchers stressed that the benefits of thiopurine treatment outweigh the risks, noting that most patients are unaffected by thiopurine-induced mutations.
Disclosure: The research was funded in part by the National Natural Science Foundation of China; National Key R&D Program of China; Shanghai Rising-Star Program; German Childhood Cancer Foundation; and ALSAC, the St. Jude fundraising and awareness organization. For full disclosures of the study authors, visit nature.com.
