The Role of DNA Repair Pathways in AML Chemosensitivity

Abstract

Background: Defects in DNA repair pathways are causal factors for a plethora of solid tumours, but are only just beginning to be explored in haematological malignancies. Genomic instability, including mutations in DNA sequences, chromosomal aneuploidy, translocations and gene amplifications contribute to the development and progression of AML. Prior DNA damaging agent exposure enhances the risk of developing AML, as does inheritance of genetic syndromes that involve alterations in DNA repair pathways. Furthermore, these same variations are associated with sensitivity and resistance to a range of chemotherapeutics. Taken together, these studies suggest that defects within DNA repair pathways are involved in the pathogenesis and prognosis of AML.

Objective: This review summarises the major DNA repair pathways, and presents an overview of current data on DNA damage repair abnormalities in AML as they pertain to the development of resistance and sensitivity to chemotherapeutics in AML. Additionally, the use of drugs that modulate these pathways as new treatments for AML will be explored herein.

Conclusion: This review highlights that abnormalities in DNA repair mechanisms in AML cells are potential novel treatment targets for AML patients with disease that is resistant to current therapies.

Keywords: Acute myeloid leukaemia; DNA repair; base excision repair.; chemosensitivity; direct enzymatic repair; homologous recombination; non-homologous end joining; nucleotide excision repair.