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SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells

Oncogene volume 32, pages 589–598 (2013)Cite this article

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Abstract

BCR-ABL transforms bone marrow progenitor cells and promotes genome instability, leading to development of chronic myelogenous leukemia (CML). The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop because of BCR-ABL mutations. Mechanisms for acquisition of BCR-ABL mutations are not fully understood. Using a novel culture model of CML acquired resistance, we show that inhibition of SIRT1 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of BCR-ABL mutations and relapse of CML cells on tyrosine kinase inhibitors. SIRT1 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin. Although SIRT1 can enhance cellular DNA damage response, it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair, in association with acquisition of genetic mutations. These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.

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Acknowledgements

This study was supported by the following Grants: W81XWH-06-1-0268 from the US Department of Defense, a career development award from the STOPCANCER Foundation, a translational research grant from the V-Foundation and R01 CA143421 from the National Cancer Institute, NIH to WYC. RB was supported by R01 CA95684, and JMS was supported by R01 CA120954. The core facilities used in this study were supported by NCI P30 CA033572.

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Author notes

  1. H Yuan

    Present address: 4Current address: Department of Stem Cell and Regenerative Medicine, Beijing Institute of Transfusion Medicine, Beijing 100850, China,

  2. Z Wang and H Yuan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA

    Z Wang, H Yuan, M Roth, J M Stark & W Y Chen

  2. Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope, Duarte, CA, USA

    R Bhatia

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Correspondence to W Y Chen.

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The contents are solely the responsibility of the authors and do not represent the official views of the National Cancer Institute or NIH. Parts of this manuscript were used for a patent application filed by City of Hope.

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Wang, Z., Yuan, H., Roth, M. et al. SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene 32, 589–598 (2013). https://doi.org/10.1038/onc.2012.83

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