DNA mismatch repair and cellular response to cytarabine :implications for the pathogenesis and treatment of therapy-related acute myeloid leukaemia

Abstract

The DNA mismatch repair (MMR) pathway is responsible for correction of replicative errors, hence is a key factor in maintenance of genomic stability. Paradoxically, functional DNA MMR also mediates the cytotoxicity of certain chemotherapeutic DNA damaging agents. Poor treatment response in therapy-related acute myeloid leukaemia (t-AML) is influenced by a number of factors, one of which might be chemoresistance due to acquired defects in DNA MMR. Using a range of paired MMR proficient and deficient cell lines, investigations herein demonstrate that DNA MMR status mediates response to nucleoside analogues such as cytarabine (Ara-C) used in t-AML chemotherapy. Interestingly, defects of specific MMR components had different and opposing effects on the cytotoxicity of these agents. These findings implicate defects of MMR components as potential prognostic factors in t-AML and suggest assessment of DNA MMR status may be warranted in individual patients when selecting treatment. Cytarabine was mutagenic to DNA at the TK and HPRT loci. Furthermore, the frequency of Ara-C-induced mutation was increased in an MMR-deficient cell line, supporting a role for MMR components in the cellular response to nucleoside analogues, and also suggesting that use of these agents themselves could contribute to the risk of t-AML development. Defective DNA MMR might also contribute to development of relapsed AML, given that genomic instability is demonstrated in some patients at relapse. Genome-wide analysis of DNA copy number aberrations and loss of heterozygosity in a small cohort of matched presentation and relapsed AML samples demonstrated a potential MMR defect in one patient, and also provided some important insights into the clonal origins of relapsed AML. The findings of these investigations together highlight several important considerations for the use of nucleoside analogues in the treatment of t-AML, as well as in other cancers in which dysfunction of the DNA MMR system is implicated.