Abstract
Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome.
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Acknowledgements
This work was carried out as part of a project grant funded by the UK Leukaemia Research Fund to MO'D and PAJ. The work was devised by MO'D and PAJ. MO'D carried out all of the experiments and wrote the article. Special thanks to David Grant (LRF) for supporting this project. MO'D's laboratory is funded by a Cancer Research UK Senior Research Fellowship and UK Medical Research Council. PAJ's laboratory is supported by the UK Medical Research Council, Human Frontiers Science Program, UK Leukaemia Research Fund, International Agency for Cancer Research, EU grant F16R-CT-2003-508842 (RiscRad) and 512113 (DNA Repair). Special thanks to all of the clinicians and scientists for discussing their LIG4 and ART-SCID BMT experiences, particularly Jean Pierre de Villartay, Despina Moshous, Nico Hartwig, Morton Cowan, Dik van Gent, Mirjam van der Burg, Stephan Ehl, Karen Cerosaletti and Sule Unal.
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O'Driscoll, M., Jeggo, P. CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair. Bone Marrow Transplant 41, 983–989 (2008). https://doi.org/10.1038/bmt.2008.18
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DOI: https://doi.org/10.1038/bmt.2008.18
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