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Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion

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Abstract

Chromosomal translocations that involve the monocytic leukemia zinc finger (MOZ) gene are typically associated with human acute myeloid leukemia (AML) and often predict a poor prognosis. Overexpression of HOXA9, HOXA10, and MEIS1 was observed in AML patients with MOZ fusions. To assess the functional role of HOX upregulation in leukemogenesis by MOZ–TIF2, we focused on bromodomain-PHD finger protein 1 (BRPF1), a component of the MOZ complex that carries out histone acetylation for generating and maintaining proper epigenetic programs in hematopoietic cells. Immunoprecipitation analysis showed that MOZ–TIF2 forms a stable complex with BRPF1, and chromatin immunoprecipitation analysis showed that MOZ–TIF2 and BRPF1 interact with HOX genes in MOZ–TIF2-induced AML cells. Depletion of BRPF1 decreased the MOZ localization on HOX genes, resulting in loss of transformation ability induced by MOZ–TIF2. Furthermore, mutant MOZ–TIF2 engineered to lack histone acetyltransferase activity was incapable of deregulating HOX genes as well as initiating leukemia. These data indicate that MOZ–TIF2/BRPF1 complex upregulates HOX genes mediated by MOZ-dependent histone acetylation, leading to the development of leukemia. We suggest that activation of BRPF1/HOX pathway through MOZ HAT activity is critical for MOZ–TIF2 to induce AML.

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Acknowledgments

This work was supported in part by Grants-in-Aid from the Ministry of Health, Labor, and Welfare; the Ministry of Education, Culture, Sports, Science, and Technology; and National Cancer Center Research and Development Fund.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Haruko Shima, Kazutsune Yamagata, Yukiko Aikawa, Mika Shino & Issay Kitabayashi

  2. Department of Developmental Genetics, RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan

    Haruhiko Koseki

  3. Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

    Haruko Shima & Hiroyuki Shimada

Authors
  1. Haruko Shima
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  2. Kazutsune Yamagata
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  3. Yukiko Aikawa
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  4. Mika Shino
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  5. Haruhiko Koseki
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  6. Hiroyuki Shimada
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  7. Issay Kitabayashi
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Correspondence to Issay Kitabayashi.

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Shima, H., Yamagata, K., Aikawa, Y. et al. Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion. Int J Hematol 99, 21–31 (2014). https://doi.org/10.1007/s12185-013-1466-x

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  • DOI: https://doi.org/10.1007/s12185-013-1466-x

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