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Acute Myeloid Leukemia

Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia

Leukemia volume 35, pages 2840–2853 (2021)Cite this article

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Abstract

Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region to partner genes in frame, producing MLL-fusions that cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as HoxA cluster and Meis1, but the underlying mechanisms remain to be fully elucidated. In this study, we discovered that Tip60, a MYST-type histone acetyltransferase, was required for the expression of HoxA cluster and Meis1 genes and the development of MLL-fusion leukemia. Tip60 was recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylated H2A.Z, thereby promoting Hoxa9 gene expression. Conditional deletion of Tip60 prevented the development of MLL-AF10 and MLL-ENL leukemia, indicating that Tip60 is indispensable for the leukemogenic activity of the MLL-AF10 and MLL-ENL-fusions. Our findings provide novel insight about epigenetic regulation in the development of MLL-AF10 and MLL-ENL-fusion leukemia.

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Fig. 1: MLL-AF10 positively regulates the ratio of acetylated H2A.Z to total H2A.Z on the Hoxa9 locus.
Fig. 2: Tip60 acetylates H2A.Z.
Fig. 3: Tip60 colocalizes with MLL-AF10 and MLL-ENL at Hoxa9 locus.
Fig. 4: Tip60 is essential for MLL-AF10 and MLL-ENL-transformed cells in vitro.
Fig. 5: Tip60 is required for development of MLL-AF10 and MLL-ENL leukemia in vivo.
Fig. 6: Tip60 globally regulates MLL-AF10 target genes.

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Acknowledgements

This work was supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE).

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Authors and Affiliations

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

    Kazutsune Yamagata, Mika Shino, Yukiko Aikawa, Shuhei Fujita & Issay Kitabayashi

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  1. Kazutsune Yamagata
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KY, MS, SF, and YA conducted the experiments; KY and IK designed the experiments and wrote the paper.

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Correspondence to Issay Kitabayashi.

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Yamagata, K., Shino, M., Aikawa, Y. et al. Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia. Leukemia 35, 2840–2853 (2021). https://doi.org/10.1038/s41375-021-01244-y

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