MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal v...

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Autores principales: Komata, Yosuke, Kanai, Akinori, Maeda, Takahiro, Inaba, Toshiya, Yokoyama, Akihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082848/
https://www.ncbi.nlm.nih.gov/pubmed/37031220
http://dx.doi.org/10.1038/s41467-023-37712-5
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author Komata, Yosuke
Kanai, Akinori
Maeda, Takahiro
Inaba, Toshiya
Yokoyama, Akihiko
author_facet Komata, Yosuke
Kanai, Akinori
Maeda, Takahiro
Inaba, Toshiya
Yokoyama, Akihiko
author_sort Komata, Yosuke
collection PubMed
description Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.
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spelling pubmed-100828482023-04-10 MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins Komata, Yosuke Kanai, Akinori Maeda, Takahiro Inaba, Toshiya Yokoyama, Akihiko Nat Commun Article Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia. Nature Publishing Group UK 2023-04-08 /pmc/articles/PMC10082848/ /pubmed/37031220 http://dx.doi.org/10.1038/s41467-023-37712-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Komata, Yosuke
Kanai, Akinori
Maeda, Takahiro
Inaba, Toshiya
Yokoyama, Akihiko
MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
title MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
title_full MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
title_fullStr MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
title_full_unstemmed MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
title_short MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
title_sort moz/enl complex is a recruiting factor of leukemic af10 fusion proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082848/
https://www.ncbi.nlm.nih.gov/pubmed/37031220
http://dx.doi.org/10.1038/s41467-023-37712-5
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AT maedatakahiro mozenlcomplexisarecruitingfactorofleukemicaf10fusionproteins
AT inabatoshiya mozenlcomplexisarecruitingfactorofleukemicaf10fusionproteins
AT yokoyamaakihiko mozenlcomplexisarecruitingfactorofleukemicaf10fusionproteins

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