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Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications

Leukemia volume 17, pages 1437–1447 (2003)Cite this article

Abstract

Mitochondrial DNA (mtDNA) codes for 13 respiratory chain subunits and is more vulnerable to damage than nuclear DNA due, in part, to a lack of histone protection and a weak repair capacity. While mtDNA alterations have been observed in human cancer, their roles in oncogenesis and chemosensitivity remain unclear. We investigated the relationship between mtDNA mutations, reactive oxygen species (ROS) generation, and clinical outcomes in chronic lymphocytic leukemia (CLL) patients. An analysis of mtDNA from 20 CLL patients revealed that primary CLL cells from patients with prior chemotherapy had a significantly higher frequency of heteroplasmic mutations than did those from untreated patients. Overall, mtDNA mutations appeared to be associated with increased ROS generation. Patients refractory to conventional therapeutic agents tended to have higher mutation rates than patients who responded to treatment. Analysis of paired blood samples from the same patient led to the identification of a heteroplasmic mutation in the cytochrome c oxidase II gene several months after chemotherapy. The mutation was associated with increased ROS generation. Our results suggest for the first time that chemotherapy with DNA-damaging agents may cause mtDNA mutations in primary leukemia cells, which often exist in heteroplasmy, and are associated with increased ROS generation.

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Acknowledgements

This study was supported in part by research Grants CA77339, CA85563, CA81534, and T32 EY07119.

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Authors and Affiliations

  1. Department of Molecular Pathology, the University of Texas MD. Anderson Cancer Center, Houston, TX, USA

    J S Carew, Y Zhou & Peng Huang

  2. Department of Hematopathology, The University of Texas MD. Anderson Cancer Center, Houston, TX, USA

    M Albitar

  3. Department of Statistics and Biostatistics, University of Wisconsin, Madison, WI, USA

    J D Carew

  4. Department of Medical Informatics, University of Wisconsin, Madison, WI, USA

    J D Carew

  5. Department of Leukemia, The University of Texas MD. Anderson Cancer Center, Houston, TX, USA

    M J Keating

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Carew, J., Zhou, Y., Albitar, M. et al. Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications. Leukemia 17, 1437–1447 (2003). https://doi.org/10.1038/sj.leu.2403043

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