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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society of Hematology
2022
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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. |
format | Online Article Text |
id | pubmed-9577624 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The American Society of Hematology |
record_format | MEDLINE/PubMed |
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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