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

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 addre...

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Autores principales: Katsumoto, Takuo, Ogawara, Yoko, Yamagata, Kazutsune, Aikawa, Yukiko, Goitsuka, Ryo, Nakamura, Takuro, Kitabayashi, Issay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9577624/
https://www.ncbi.nlm.nih.gov/pubmed/35947126
http://dx.doi.org/10.1182/bloodadvances.2020003490
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author Katsumoto, Takuo
Ogawara, Yoko
Yamagata, Kazutsune
Aikawa, Yukiko
Goitsuka, Ryo
Nakamura, Takuro
Kitabayashi, Issay
author_facet Katsumoto, Takuo
Ogawara, Yoko
Yamagata, Kazutsune
Aikawa, Yukiko
Goitsuka, Ryo
Nakamura, Takuro
Kitabayashi, Issay
author_sort Katsumoto, Takuo
collection PubMed
description 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.
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spelling pubmed-95776242022-10-28 MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression Katsumoto, Takuo Ogawara, Yoko Yamagata, Kazutsune Aikawa, Yukiko Goitsuka, Ryo Nakamura, Takuro Kitabayashi, Issay Blood Adv Regular Article 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. The American Society of Hematology 2022-08-12 /pmc/articles/PMC9577624/ /pubmed/35947126 http://dx.doi.org/10.1182/bloodadvances.2020003490 Text en © 2022 by The American Society of Hematology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular Article
Katsumoto, Takuo
Ogawara, Yoko
Yamagata, Kazutsune
Aikawa, Yukiko
Goitsuka, Ryo
Nakamura, Takuro
Kitabayashi, Issay
MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression
title MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression
title_full MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression
title_fullStr MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression
title_full_unstemmed MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression
title_short MOZ is critical for the development of MOZ/MLL fusion–induced leukemia through regulation of Hoxa9/Meis1 expression
title_sort moz is critical for the development of moz/mll fusion–induced leukemia through regulation of hoxa9/meis1 expression
topic Regular Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9577624/
https://www.ncbi.nlm.nih.gov/pubmed/35947126
http://dx.doi.org/10.1182/bloodadvances.2020003490
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