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DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance

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Abstract

DNA damage repair mechanisms are vital to maintain genomic integrity. Mutations in genes involved in the DNA damage response (DDR) can increase the risk of developing cancer. In recent years, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia (AML) or of disease relapse. Moreover, a growing body of literature has indicated that epigenetic silencing of DDR genes could contribute to the leukemogenic process. In addition, a variety of AML oncogenes have been shown to induce replication and oxidative stress leading to accumulation of DNA damage, which affects the balance between proliferation and differentiation. Conversely, upregulation of DDR genes can provide AML cells with escape mechanisms to the DDR anticancer barrier and induce chemotherapy resistance. The current review summarizes the DDR pathways in the context of AML and describes how aberrant DNA damage response can affect AML pathogenesis, disease progression, and resistance to standard chemotherapy, and how defects in DDR pathways may provide a new avenue for personalized therapeutic strategies in AML.

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Acknowledgments

We would like to thank Profs. Sidney Shall, Axel Behrens, and Fabrizio d’Adda Di Fagagna for helpful discussion and critical comments. This work is supported by Leukemia and Lymphoma Research (LLR) and Cancer Research UK (CRUK).

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  1. Leukemia and Stem Cell Biology Group, Department of Hematological Medicine, King’s College London, Denmark Hill campus, SE5 9NU, London, UK

    Maria Teresa Esposito & Chi Wai Eric So

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Correspondence to Chi Wai Eric So.

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Esposito, M.T., So, C.W.E. DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance. Chromosoma 123, 545–561 (2014). https://doi.org/10.1007/s00412-014-0482-9

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