Tracking the evolution of therapy-related myeloid neoplasms using chemotherapy signatures

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 McPhersonMikkael 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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was 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 after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed 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 preexisting CH but also promote the acquisition of recurrent genomic drivers.

Original languageEnglish
Pages (from-to)2359-2371
Number of pages13
JournalBlood
Volume141
Issue number19
DOIs
StatePublished - May 11 2023

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