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Oncogenes, Fusion Genes and Tumor Suppressor Genes

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

Leukemia volume 26, pages 303–311 (2012)Cite this article

Abstract

Loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Although several reports have suggested roles for RUNX1 as a tumor suppressor, its precise function remains unknown. Because gene alterations of RUNX1 by themselves do not lead to the development of leukemia in mouse models, additional mutation(s) would be required for leukemia development. Here, we report that the C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. γH2AX foci, which indicate the presence of DNA double-strand breaks, were more abundantly accumulated in RUNX1dC-transduced lineage−Sca1+c-kit+ (LSK) cells than in mock-transduced LSK cells both in a steady state and after γ-ray treatment. Expression profiling by real-time -PCR array revealed RUNX1dC represses the expression of Gadd45a, a sensor of DNA stress. Furthermore, bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A and that RUNX1 and p53 synergistically activate the GADD45A transcription. Together, these results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation(s) required for multi-step leukemogenesis.

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Acknowledgements

We thank the Department of Dermatology, Osaka University Graduate School of Medicine for help with UV-B-exposure experiments, Y Sowa and T Sakai for help with reporter assays of Gadd45a, and J Yamauchi for technical advice. We appreciate discussions with and suggestions of C Masutani, K Oritani, T Yokota and S Ezoe. This research was supported in part by a Grant-in Aid for Scientific Research (C) (to Y Satoh), a Grant-in Aid for Scientific Research (B) (to I Matsumura) from MEXT and by the Sankyo Foundation of Life Science.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan

    Y Satoh, K Matsui, M Shibata, M Mizuki & Y Kanakura

  2. Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Kinki University, Osaka-sayama, Japan

    I Matsumura & H Tanaka

  3. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    H Harada

  4. International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Y Harada

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Satoh, Y., Matsumura, I., Tanaka, H. et al. C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells. Leukemia 26, 303–311 (2012). https://doi.org/10.1038/leu.2011.202

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