Mutational impact of chemotherapy on hematopoietic cells and evolution towards therapy-related pediatric AML

The long-term survival rate of childhood cancer has increased to over 80%, largely due to chemotherapy as a major treatment modality. Chemotherapy acts predominantly by fatally damaging DNA of malignant cells; however, the mutational effects in normal tissues remain unknown. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPCs) of 23 pediatric cancer patients, of which 18 developed therapy-related myeloid neoplasms later in life. Phylogenetic inference demonstrated that during chemotherapy exposure mutant HSPC clones are induced and selected, which may ultimately contribute to therapy-related acute myeloid leukemia (t-AML). Post-treatment HSPCs showed a significantly increased mutation load compared to treatment-naïve cells. Mutational signature extraction revealed that only few chemotherapeutic drugs, such as platinum drugs and thiopurines, caused direct mutagenic effects. While cisplatin affected all exposed cells, thiopurine affected leukemic blasts and MLL-rearranged HSPCs. Intriguingly, increased mutagenesis in most patients was caused by processes similar to those underlying clock-like signatures also present during normal aging.

Publication History

Article published online:
17 May 2022