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Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia

Leukemia volume 15, pages 1898–1905 (2001)Cite this article

Abstract

There is continued controversy as to the sequential steps and mechanism(s) responsible for the in vivo acquisition of multiple mutations during neoplastic transformation. We investigated the in vivo clonality and mutational spectra of hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations in T cells from children with acute lymphocytic leukemia (ALL) to gain insight into the mutagenic mechanisms associated with leukemogenesis. We observed several instances of multiple, independent HPRT mutations accumulating in vivo in T cell receptor (TCR) gene defined clones that had undergone extensive pre- and/or post-thymic expansion following chemotherapy. In addition, we also detected the accumulation of multiple unique single mutations within distinct expanding post-thymic T cell clones. This pattern of clonally restricted hypermutability is compatible with extensive cell proliferation and selection alone without postulating genomic instability. These observations provide a paradigm for a continuum of cellular events that eventually results in the clonal accumulation of mutations in selected populations of cells in vivo and may provide insight into the primary genetic events associated with leukemogenesis, as well as the development of second malignancies and drug resistance following chemotherapy.

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Acknowledgements

We thank S Billado RPN, for assistance with obtaining blood samples, and Chung-Chen Durieux-Lu for technical assistance. This work was supported by National Institute for Child Health and Human Development grant 1R29HD35309, Grant 6103–98 from the Leukemia and Lymphoma Society, National Cancer Institute grant 1K01CA77737NCI and P30CA22435 to the University of Vermont Cancer Center DNA Analysis Facility.

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Authors and Affiliations

  1. Department of Pediatrics, University of Vermont, Burlington, VT, USA

    BA Finette, AC Homans, J Rivers & T Messier

  2. Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, USA

    BA Finette

  3. Department of Pathology, University of Vermont, Burlington, VT, USA

    RJ Albertini

  4. Vermont Cancer Center, University of Vermont, Burlington, VT, USA

    BA Finette, AC Homans, J Rivers, T Messier & RJ Albertini

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Finette, B., Homans, A., Rivers, J. et al. Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia. Leukemia 15, 1898–1905 (2001). https://doi.org/10.1038/sj.leu.2402306

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