Chemotherapy can induce mutations that lead to pediatric leukemia relapse

A new study has found that a group of chemotherapy drugs can result in mutations that may trigger the relapse of blood cancer in children.Chemotherapy has helped make acute lymphoblastic leukemia (ALL) one of the most survivable childhood cancers. Now, researchers working in the US, Germany and China have shown how chemotherapy drugs called thiopurines can lead to mutations that set patients up for relapse. The findings of the study were published in the journal ‘Nature Cancer’.

The research provided 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. “The findings offer a paradigm shift in understanding how drug resistance develops,” said Jinghui Zhang, PhD, Department of Computational Biology chair at St. Jude Children’s Research Hospital.

“The results also suggest possible treatment strategies for ALL patients who relapse, including screening to identify those who should avoid additional thiopurine treatment,” added Zhang. Zhang is co-corresponding author of the study with Bin-Bing Zhou, Ph.D., of Shanghai Children’s Medical Center; and Renate Kirschner-Schwabe, M.D., of Charite-Universitaetsmedizin Berlin.

THE ROOTS OF RELAPSE

While 94 per cent of St. Jude patients with ALL become five-year survivors, relapse remains the leading cause of death worldwide for children and adolescents with ALL. This study involved ALL samples collected from relapsed pediatric ALL patients in the US, China and Germany. Researchers analysed 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, 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 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 tumour suppressor gene TP53. The mutation, TP53 R248Q, promoted resistance to multiple chemotherapy drugs, including vincristine, daunorubicin and cytarabine.