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ACUTE MYELOID LEUKEMIA

Genetic and chemical targeting of the ATPase complex TIP48 and 49 impairs acute myeloid leukemia

Leukemia volume 37, pages 1812–1829 (2023)Cite this article

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Abstract

The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.

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Fig. 1: Loss of Tip48 or Tip49 leads to an embryonic lethal.
Fig. 2: Tip48/49 complex is required for leukemogenesis.
Fig. 3: Chemical inhibition of Tip48/49 ATPase activity inhibits leukemia growth.
Fig. 4: Loss of Tip48/49 induces apoptosis.
Fig. 5: p53 dependent apoptosis is regulated by Tip48/49.

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Acknowledgements

We thank Dr. Toshio Imai at the Central Animal Division for maintaining animals, Dr. Masamichi Ishiai at The Central Radioisotope Division for advice on radioisotope use, Rie Sawado and Yukiko Aikawa for technical help, and Drs. Takahiro Ito and Myriam Y Hsu for comments on the manuscript. This work was supported by AMED (JP19cm0106141 and JP21cm010617), JSPS KAKENHI (JP22H03103), the Japan Science and Technology Agency (grant JPMJMS2022-16) and 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, Tokyo, Japan

    Ayuna Hattori, Emi Takamatsu-Ichihara, Shuhei Fujita, Kazutsune Yamagata, Takuo Katsumoto, Haruka Shinohara & Issay Kitabayashi

  2. Division of Cell Fate Dynamics and Therapeutics, Department of Biosystems Science, Institute for Life and Medical Sciences (LiMe), Kyoto University, Kyoto, Japan

    Ayuna Hattori & Yoshiki Yamamoto

  3. Department of Veterinary Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan

    Yukino Machida

  4. Oncology Research Laboratory II, Daiichi Sankyo Co., Ltd, Tokyo, Japan

    Ryo Murakami

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  1. Ayuna Hattori
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Contributions

AH designed the study, performed all experiments, analyzed the data, and wrote the manuscript. ET-I generated Tip48 and Tip49 cKO mice. YY performed western blotting, immunofluorescence, and bioinformatics analysis. SF and YM performed part of drug treatment analysis. RM provided the compound. KY, TK and HS contributed essential reagents. IK conceived and supervised the project. All authors read and edited manuscript.

Corresponding authors

Correspondence to Ayuna Hattori or Issay Kitabayashi.

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Competing interests

RM is an employee of Daiichi Sankyo, Co., Ltd. All other authors declare no conflict of interest.

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Hattori, A., Takamatsu-Ichihara, E., Yamamoto, Y. et al. Genetic and chemical targeting of the ATPase complex TIP48 and 49 impairs acute myeloid leukemia. Leukemia 37, 1812–1829 (2023). https://doi.org/10.1038/s41375-023-01971-4

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