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Deregulation of homologous recombination DNA repair in alkylating agent-treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia

Oncogene volume 25, pages 1709–1720 (2006)Cite this article

Abstract

Chemotherapeutic regimes involving alkylating agents, such as methylators and crosslinking nitrogen mustards, represent a major risk factor for acute myeloid leukaemia. A high frequency of microsatellite instability and evidence of MSH2 loss in alkylating chemotherapy-related acute myeloid leukaemia (t-AML) suggests that DNA mismatch repair (MMR) dysfunction may be an initiating event in disease evolution. Subsequent accumulation of secondary genetic changes as a result of DNA MMR loss may ultimately lead to the gross chromosomal abnormalities seen in t-AML. Homologous recombination repair (HRR) maintains chromosomal stability by the repair of DNA double-strand breaks, and is therefore a possible target for deregulation in MMR dysfunctional t-AML. In order to test this hypothesis Msh2- proficient and -deficient murine embryonic stem (ES) cells were used to examine the effects of MMR status and methylating agent treatment on cellular expression of DNA double-strand break repair genes. HRR gene expression was significantly deregulated in Msh2 null ES cell clones compared to wild-type clones. Furthermore, some Msh2 null clones expressed high levels of Rad51 specifically, a critical component of HRR. Such Rad51 superexpressing clones were also observed when expression was determined in monocytic myeloid cells differentiated from ES cells. A deregulated HRR phenotype could be partially recapitulated in MMR-competent wild-type cells by treatment with the methylating agent, N-methyl-N-nitrosourea. Furthermore, treatment with melphalan, a leukaemogenic DNA crosslinking chemotherapy nitrogen mustard predicted to elicit HRR, selected against cells with deregulated HRR. These data suggest a t-AML mechanism whereby DNA MMR loss promotes the emergence of HRR gene superexpressing clones, with concomitant chromosomal instability. However, melphalan selection against clones with deregulated HRR suggests that persistence and expansion of unstable clones may require additional genetic alterations that promote cell survival.

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Acknowledgements

We thank Fiona Mensah and Alexandra Smith (Epidemiology and Genetics Unit, York University), for their assistance with the statistical analysis, and Sheila O'Connor (Haematological Malignancy Diagnostic Unit, Leeds General Infirmary) for her assistance in monocyte identification. We also acknowledge the excellent technical support provided by Celina Whalley and Barbara Smith (Technology Facility, York University). We also thank Professor Constance Bonifer and Debbie Clarke (Molecular Medicine Unit, University of Leeds), and Professor Hein te Reile (Netherlands Cancer Institute, Amsterdam). This work was supported by the Leukaemia Research Fund.

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  1. Department of Biology, Epidemiology and Genetics Unit, University of York, York, North Yorkshire, UK

    L J Worrillow & J M Allan

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Correspondence to J M Allan.

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Worrillow, L., Allan, J. Deregulation of homologous recombination DNA repair in alkylating agent-treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia. Oncogene 25, 1709–1720 (2006). https://doi.org/10.1038/sj.onc.1209208

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