MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression

Takuo Katsumoto, Yoko Ogawara, Kazutsune Yamagata, Yukiko Aikawa, Ryo Goitsuka, Takuro Nakamura, Issay Kitabayashi

研究成果: ジャーナルへの寄稿学術論文査読

7 被引用数 (Scopus)

抄録

Monocytic leukemia zinc finger protein (MOZ, MYST3, or KAT6A) is a MYST-type acetyltransferase involved in chromosomal translocation in acute myelogenous leukemia (AML) and myelodysplastic syndrome. MOZ is established as essential for hematopoiesis; however, the role of MOZ in AML has not been addressed. We propose that MOZ is critical for AML development induced by MLL-AF9, MLL-AF10, or MOZ-TIF2 fusions. Moz-deficient hematopoietic stem/progenitor cells (HSPCs) transduced with an MLL-AF10 fusion gene neither formed colonies in methylcellulose nor induced AML in mice. Moz-deficient HSPCs bearing MLL-AF9 also generated significantly reduced colony and cell numbers. Moz-deficient HSPCs expressing MOZ-TIF2 could form colonies in vitro but could not induce AML in mice. By contrast, Moz was dispensable for colony formation by HOXA9-transduced cells and AML development caused by HOXA9 and MEIS1, suggesting a specific requirement for MOZ in AML induced by MOZ/MLL fusions. Expression of the Hoxa9 and Meis1 genes was decreased in Moz-deficient MLL fusion-expressing cells, while expression of Meis1, but not Hoxa9, was reduced in Moz-deficient MOZ-TIF2 AML cells. AML development induced by MOZ-TIF2 was rescued by introducing Meis1 into Moz-deficient cells carrying MOZ-TIF2. Meis1 deletion impaired MOZ-TIF2–mediated AML development. Active histone modifications were also severely reduced at the Meis1 locus in Moz-deficient MOZ-TIF2 and MLL-AF9 AML cells. These results suggest that endogenous MOZ is critical for MOZ/MLL fusion-induced AML development and maintains active chromatin signatures at target gene loci.

本文言語英語
ページ(範囲)5527-5537
ページ数11
ジャーナルBlood Advances
6
19
DOI
出版ステータス出版済み - 11-10-2022
外部発表はい

All Science Journal Classification (ASJC) codes

  • 血液学

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