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DNA damage check points prevent leukemic transformation in myelodysplastic syndrome

Leukemia volume 21, pages 2195–2198 (2007)Cite this article

Cells constantly suffer DNA damage caused by agents such as free oxygen radicals, natural ionizing radiation or unscheduled replicative stimuli induced by aberrant oncogene activation. The cellular response to these stresses plays a critical role for maintenance of genome integrity. Cellular DNA in mammalian cells under constant DNA-damaging stress always carries the risk of mutation. Initially, genetic alternations may take place in genes with potential oncogenic activity, which may then begin progression towards transformation. Oncogenic stimuli enforce cell proliferation, which requires DNA replication. Unscheduled DNA replication enforced by oncogenic stimuli activates a signal for stalled replication, leading to single-strand breaks and subsequently to double-strand breaks on DNA. This DNA damage facilitates activation of DNA damage check point pathways including ataxia telangiectasia mutated (ATM) and/or ataxia telangiectasia Rad3 related (ATR), which can then lead to cell cycle arrest, apoptosis, repair or cell senescence. However, once DNA damage has occurred in genes playing a crucial role in the DNA damage response itself, the DNA damage check point pathway is compromised and the cells acquire a growth advantage and can undergo transformation more readily. Such cells, manifesting genomic instability, thus start to proliferate and accumulate additional complex mutations. Tumorigenesis evolves stepwise in this fashion.1, 2 ATM protein kinase is activated by intermolecular autophosphorylation in response to DNA damage and initiates cellular responses thereto. This activation status of DNA damage check point can be determined by measuring phosphorylation status of histone H2AX at Ser 139 (γ-H2AX), phospho-Ser 1981 ATM and downstream Chk2 at Thr 67 and p53 at Ser 15. The phosphorylation of these substrates can be monitored by respective phospho-specific antibodies.

Myelodysplastic syndrome (MDS) is a clonal malignant hematological disorder characterized by ineffective hematopoiesis and reflects a preleukemic condition. Approximately 40–50% of MDS patients develop overt leukemia (OL) after several years of latency.3

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Acknowledgements

We thank Ms Inoue and Ms Hasegawa for technical assistance. This work was supported by a Grant-in-aid from the Ministry of Education, Science and Culture. MT is supported by a Grant-in-aid from Japanese Leukemia Research Fund.

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Authors and Affiliations

  1. Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    S Horibe, M Takagi, J Unno, M Nagasawa, T Morio & S Mizutani

  2. Department of Pediatrics, International University of Health and Welfare Mita Hospital, Minato-ku, Tokyo, Japan

    M Takagi

  3. Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    A Arai & O Miura

  4. Department of Hematology, Tokyo Metropolitan Geriatric Medical Center, Itabashi-ku, Tokyo, Japan

    M Ohta

  5. Department of Comprehensive Pathology, Aging and Developmental Sciences, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    M Kitagawa

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  1. S Horibe
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Correspondence to M Takagi or S Mizutani.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Horibe, S., Takagi, M., Unno, J. et al. DNA damage check points prevent leukemic transformation in myelodysplastic syndrome. Leukemia 21, 2195–2198 (2007). https://doi.org/10.1038/sj.leu.2404748

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