AML-743 Germline Homologous Recombination Deficiency (HRD) Influences the Fitness Impact of Oncologic Therapy on DNA Damage Response Gene Clonal Hematopoiesis (CH)
- Abstract:
- Context Previous studies have linked poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents to therapy-related myeloid neoplasia. However, interpretation of these findings is limited by confounding variables, including germline status and prior therapy. We hypothesized that exposure to PARPi confers a competitive advantage to hematopoietic stem/progenitor cells (HSPCs) containing mutations in DNA damage response (DDR) genes. Moreover, in patients with germline mutations in HRD genes, genotoxic stress induced by PARPi may be increased, further enhancing the fitness of HSPCs carrying DDR gene mutations. Methods We performed longitudinal studies on peripheral blood samples collected from 418 patients before and after treatment with PARPi or carboplatin. We also developed a chimeric mouse model of Trp53-mutated CH. The percentage of Trp53-mutant cells was measured by flow cytometry before and after treatment with vehicle, talazoparib, olaparib, or cisplatin. Results In patients, both carboplatin and PARPi treatment significantly increased the growth of CH mutations, driven almost entirely by mutations in DDR genes. The strongest PARP-trapping member, talazoparib, had the largest effect on the growth rate of CH mutations in DDR genes but was lower than carboplatin. Surprisingly, DDR-CH expansion was largely abrogated in patients harboring a germline HRD mutation, for both carboplatin and PARPi. In the mouse model, treatment with cisplatin resulted in a significant expansion of Trp53-mutated leukocytes and HSPCs. A smaller but significant increase was also observed after talazoparib but not olaparib. We next modeled the effect of germline HRD mutations in mice containing Brca1 +/- bone marrow competed with Brca1 +/-/Trp53-mutant bone marrow. Consistent with the human CH data, no expansion of Trp53-mutated leukocytes or HSPCs was observed after treatment with cisplatin or talazoparib. Conclusion Collectively, these data support the hypothesis that mutations in DDR genes provide a fitness advantage to HSPCs following PARPi and platinum therapy. However, PARPi shows less selective pressure on DDR CH than platinum. Importantly, these data strongly argue that germline HRD variants do not enhance this fitness advantage. PARPi therapy may have less of an impact on leukemia risk compared to carboplatin and may synergize with HRD in blocking the competitive advantage of DDR CH during genotoxic stress.
- Authors:
- JT Baeten, ICC Chan, L Moukarzel, AC Carter, M Patel, K Stopsack, P Pharoah, J Brenton, B Li, W Abida, A Schram, K Cadoo, B Weigelt, C Cruchaga, H Scher, R Levine, E Papaemmanuil, DC Link, KL Bolton
- Journal:
- Clinical Lymphoma Myeloma & Leukemia
- Citation info:
- 24:s336
- Publication date:
- 1st Sep 2024
- Full text
- DOI