Chemotherapy-induced genotoxic damage to bone marrow cells: long-term implications

Area of Science:

• Oncology
• Stem Cell Biology
• Genotoxicology

Background:

• Mesenchymal stem/stromal cells (MSCs) are crucial for hematopoiesis and the bone marrow micro-environment.
• Chemotherapy is known to damage MSCs phenotypically and functionally.
• The long-term genotoxic effects of chemotherapy on the bone marrow micro-environment remain understudied.

Purpose of the Study:

• To evaluate the persistent genotoxic effects of chemotherapy on the bone marrow micro-environment.
• To investigate DNA damage in MSCs and other bone marrow cells in vitro and in vivo after chemotherapy exposure.
• To assess the potential contribution of persistent DNA lesions to patient complications.

Main Methods:

• In vitro exposure of MSC cell line (HS-5) and cord blood mononuclear cells (CBMNCs) to cyclophosphamide (CY).
• In vivo analysis of bone marrow cells from chemotherapy-treated patients.
• Comet assay and micronucleus assay were used to measure DNA damage.

Main Results:

• CY treatment significantly increased DNA damage in both CBMNCs and HS-5 cells in vitro.
• DNA damage persisted in treated cells up to 48 hours after CY removal.
• Patients showed significant increases in damaged DNA in bone marrow cells one year post-chemotherapy, and in MSCs 7-17 years after treatment.

Conclusions:

• Chemotherapy induces persistent genotoxic effects on bone marrow MSCs.
• Long-term DNA damage to MSCs may compromise stem cell transplant engraftment.
• Persistent DNA lesions could contribute to therapy-related malignancies due to genetic instability.