Cytarabine preferentially induces mutation at specific sequences in the genome which are identifiable in relapsed acute myeloid leukaemia

Abstract

Cytarabine (1-β-D-arabinofuranosylcytosine; Ara-C) is an effective remission induction treatment for acute myeloid leukemia (AML).1,2 However, the majority of patients relapse within 3 years, often with aggressive AML2 characterised by the gain of novel base substitution mutations in genes including IDH2 and TET2.3,4 Chemotherapy used to treat AML is predicted to induce mutations detectable in relapsed disease, although direct evidence for this is lacking. The cytotoxicity of Ara-C is mediated in part by incorporation into replicating DNA leading to inhibition of chain extension. However, even at concentrations that induce significant cell death, arabinofuranosylcytosine triphosphate, the reactive metabolite of Ara-C, is primarily incorporated into DNA at internucleotide positions,5,6 suggesting that this nucleoside analogue is likely mutagenic and could contribute to the aetiology of novel somatic mutations acquired during AML relapse.