Benjamin Diamond, Bachisio Ziccheddu, Kylee Maclachlan, Justin Taylor, Eileen Boyle, Juan Arango Ossa, Jacob Jahn, Maurizio Affer, Tulasigeri M Totiger, David Coffey, Namrata Chandhok, Justin Watts, Luisa Cimmino, Sydney X Lu, Niccolò Bolli, Kelly Bolton, Heather Landau, Jae H Park, Karuna Ganesh, Andrew McPherson, Mikkael A Sekeres, Alexander Lesokhin, David J Chung, Yanming Zhang, Caleb Ho, Mikhail Roshal, Jeffrey Tyner, Stephen Nimer, Elli Papaemmanuil, Saad Usmani, Gareth Morgan, Ola Landgren, Francesco Maura

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures 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 hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient's life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.