Abstract 1962: DNA mismatch repair status modulates cellular response to cytarabine: Implications for treatment of acute myeloid leukemia
Authors: Sarah Fordham, Elizabeth Matheson, Kathryn Scott, Julie Irving, James Allan
Journal: Cancer Research (2010)

Abstract The DNA mismatch repair (MMR) pathway is responsible for repair of spontaneous errors arising during DNA replication, thus maintaining the integrity of the genome. DNA MMR is frequently dysregulated in some forms of leukemia. We and others have shown that microsatellite instability, the hallmark of dysfunctional DNA MMR, is present in up to 90% of therapy-related myeloid leukemia, 50% of relapsed myeloid leukemia, but is rarely seen in de novo leukemia. Paradoxically, functional MMR mediates the cytotoxicity of certain chemotherapeutic agents, particularly methylating agents and the nucleoside analogue 6-thioguanine, and dysregulation of the MMR pathway confers tolerance to these agents. In the present study, using cell lines harbouring defects in MMR components, we show that MMR status also modulates response to the nucleoside analogue cytarabine and to other therapeutic nucleoside analogues commonly used in the treatment of leukemia. We have determined gene and protein expression levels of the major MMR components in a panel of 4 psuedo-isogenic cell line pairs, and investigated the ability of cell extracts to bind to defined mismatches in electrophoretic mobility shift assays. The cell lines HL-60R (which demonstrates 200-fold overexpression of MSH3) and MT-1 (which lacks functional MSH6 due to bi-allelic gene mutation) were tolerant to the cytotoxic effects of methylating agents and 6-thioguanine by virtue of loss of MutSα activity. However, two additional cell lines, TK6 MTXR and PreB697 MTXR (which demonstrate approximately 5-fold and 2-fold overexpression of MSH3 respectively), did not demonstrate differential response to the cytotoxic effects of methylating agent or 6-thioguanine, suggesting that relatively modest MMR defects do not significantly perturb the pathway. Consistent with a role for MMR in affecting cellular response to other nucleoside analogues used to treat leukemia, those cell lines with major defects in MMR (HL-60R and MT-1) displayed differential toxicity to the killing effects of cytarabine, clofarabine, cladribine and fludarabine compared to their MMR-proficient parental counterparts. In contrast, those cell lines with modest perturbation of the MMR pathway did not respond differently to their parental counterparts following treatment with these agents. Taken together, these data suggest that cellular MMR status affects response to nucleoside analogues and furthermore, the specific nature of the defect is important in determining the exact response. These findings have implications for the use of nucleoside analogues in the treatment of cancers where MMR dysfunction has been identified to occur with high frequency, such as therapy-related and relapsed acute myeloid leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1962.