Abstract

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms1, 2. Pre-leukemic clones (i.e., clonal hematopoiesis) are detectable years before the development of these aggressive malignancies3-5, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures6-12 from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are relatively hypermutated and enriched for complex structural variants (i.e., chromothripsis), while neoplasms with alternative exposures bear a similar profile to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as a temporal barcode in each patients life, we estimate that several complex events and genomic drivers are acquired after chemotherapy exposure. In the case of treatment with high-dose melphalan and autologous stem cell transplantation, we demonstrate that the procedure allows clonal hematopoiesis to escape chemotherapy exposure entirely, and to be reinfused to expand to malignancy. This information reveals a novel mode of malignant progression for therapy-related malignancies that is not reliant on direct mutagenesis or even exposure to chemotherapy, itself, and prompts further investigation into leukemia-permissive effects of cytotoxic drugs.