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

Ayuna Hattori, Emi Takamatsu-Ichihara, Yoshiki Yamamoto, Shuhei Fujita, Kazutsune Yamagata, Takuo Katsumoto, Yukino Machida, Haruka Shinohara, Ryo Murakami, Issay Kitabayashi

研究成果: ジャーナルへの寄稿学術論文査読

1 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)1812-1829
ページ数18
ジャーナルLeukemia
37
9
DOI
出版ステータス出版済み - 09-2023
外部発表はい

All Science Journal Classification (ASJC) codes

  • 血液学
  • 腫瘍学
  • 癌研究

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