Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms.
Eline J M BertrumsJurrian K de KanterLucca L M DerksMark VerheulLaurianne TrabutMarkus J van RoosmalenHenrik HasleEvangelia AntoniouDirk ReinhardtMichael N DworzakNora MühleggerMarry M M van den Heuvel-EibrinkC Michel ZwaanBianca Frederika GoemansRuben van BoxtelPublished in: Nature communications (2024)
Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.
Keyphrases
- single cell
- locally advanced
- young adults
- room temperature
- metal organic framework
- bone marrow
- rna seq
- transition metal
- acute myeloid leukemia
- dna repair
- early stage
- dendritic cells
- cancer therapy
- combination therapy
- radiation therapy
- squamous cell carcinoma
- childhood cancer
- high throughput
- drug induced
- oxidative stress
- drug delivery
- case report
- mesenchymal stem cells
- air pollution
- rectal cancer
- copy number
- genome wide
- diabetic rats
- solid state