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DNA mismatch repair status affects cellular response to Ara-C and other anti-leukemic nucleoside analogs

Leukemia volume 25, pages 1046–1049 (2011)Cite this article

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Nucleoside analogs form the backbone of therapeutic regimes for acute myeloid leukemia (AML) and are used to treat numerous other hematological malignancies, including B-cell acute lymphoblastic leukemia and Hodgkin lymphoma. Chemoresistance presents a major obstacle to the successful treatment of both relapsed and therapy-related AML (t-AML), and altered DNA repair function is one possible mechanism underlying this phenotype.

Microsatellite instability, indicative of defective DNA mismatch repair (MMR) is a rare finding in de novo AML but is common in relapsed AML and t-AML, in which it is reported to occur in 30–90% of cases.1, 2, 3 DNA MMR is responsible for maintaining the integrity of the genome by mediating repair of spontaneous DNA damage arising during DNA replication. The MutSα heterodimer (comprising hMSH2 and hMSH6) initiates repair of base/base mispairs. A second complex, MutSβ (comprising hMSH2 and hMSH3), mediates repair of short- and long insertion-deletion loops, but has no activity toward mispairs. Subsequent recruitment of the MutLα heterodimer (hMLH1 and hPMS2) facilitates strand excision and gap filling, restoring the DNA to its original structure. Paradoxically, functional DNA MMR facilitates cytotoxicity of certain chemotherapeutic agents, including methylating agents and the base analog 6-thioguanine (6-TG). In both the cases, the mechanisms leading to cell death remain unclear, although one hypothesis suggests that recognition of O6-MeG:T or Me6-TG:T mispairs in DNA by MutSα leads to repeated abortive repair, ultimately resulting in the formation of pro-cytotoxic DNA strand breaks.1 MMR-defective cells lack the capacity to recognize mispairs and consequently demonstrate a ‘tolerant’ phenotype and chemoresistance.

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Acknowledgements

This work was supported by Leukemia and Lymphoma Research, UK (Grant no. 06002 to JMA).

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Authors and Affiliations

  1. Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK

    S E Fordham, E C Matheson, J A E Irving & J M Allan

  2. Department of Biology, University of York, York, UK

    K Scott

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  1. S E Fordham
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Correspondence to J M Allan.

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Fordham, S., Matheson, E., Scott, K. et al. DNA mismatch repair status affects cellular response to Ara-C and other anti-leukemic nucleoside analogs. Leukemia 25, 1046–1049 (2011). https://doi.org/10.1038/leu.2011.38

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