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Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development

Acute myeloid leukemia (AML) is an aggressive blood cancer that stems from the rapid expansion of immature leukemic blasts in the bone marrow. Mutations in epigenetic factors represent the largest category of genetic drivers of AML. The chromatin assembly factor CHAF1B is a master epigenetic regulat...

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Autores principales: Dean, Sarai T., Ishikawa, Chiharu, Zhu, Xiaoqin, Walulik, Sean, Nixon, Timothy, Jordan, Jessica K., Henderson, Samantha, Wyder, Michael, Salomonis, Nathan, Wunderlich, Mark, Greis, Kenneth D., Starczynowski, Daniel T., Volk, Andrew G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10469560/
https://www.ncbi.nlm.nih.gov/pubmed/37205848
http://dx.doi.org/10.1182/bloodadvances.2022009438
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author Dean, Sarai T.
Ishikawa, Chiharu
Zhu, Xiaoqin
Walulik, Sean
Nixon, Timothy
Jordan, Jessica K.
Henderson, Samantha
Wyder, Michael
Salomonis, Nathan
Wunderlich, Mark
Greis, Kenneth D.
Starczynowski, Daniel T.
Volk, Andrew G.
author_facet Dean, Sarai T.
Ishikawa, Chiharu
Zhu, Xiaoqin
Walulik, Sean
Nixon, Timothy
Jordan, Jessica K.
Henderson, Samantha
Wyder, Michael
Salomonis, Nathan
Wunderlich, Mark
Greis, Kenneth D.
Starczynowski, Daniel T.
Volk, Andrew G.
author_sort Dean, Sarai T.
collection PubMed
description Acute myeloid leukemia (AML) is an aggressive blood cancer that stems from the rapid expansion of immature leukemic blasts in the bone marrow. Mutations in epigenetic factors represent the largest category of genetic drivers of AML. The chromatin assembly factor CHAF1B is a master epigenetic regulator of transcription associated with self-renewal and the undifferentiated state of AML blasts. Upregulation of CHAF1B, as observed in almost all AML samples, promotes leukemic progression by repressing the transcription of differentiation factors and tumor suppressors. However, the specific factors regulated by CHAF1B and their contributions to leukemogenesis are unstudied. We analyzed RNA sequencing data from mouse MLL-AF9 leukemic cells and bone marrow aspirates, representing a diverse collection of pediatric AML samples and identified the E3 ubiquitin ligase TRIM13 as a target of CHAF1B-mediated transcriptional repression associated with leukemogenesis. We found that CHAF1B binds the promoter of TRIM13, resulting in its transcriptional repression. In turn, TRIM13 suppresses self-renewal of leukemic cells by promoting pernicious entry into the cell cycle through its nuclear localization and catalytic ubiquitination of cell cycle–promoting protein, CCNA1. Overexpression of TRIM13 initially prompted a proliferative burst in AML cells, which was followed by exhaustion, whereas loss of total TRIM13 or deletion of its catalytic domain enhanced leukemogenesis in AML cell lines and patient-derived xenografts. These data suggest that CHAF1B promotes leukemic development, in part, by repressing TRIM13 expression and that this relationship is necessary for leukemic progression.
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spelling pubmed-104695602023-09-01 Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development Dean, Sarai T. Ishikawa, Chiharu Zhu, Xiaoqin Walulik, Sean Nixon, Timothy Jordan, Jessica K. Henderson, Samantha Wyder, Michael Salomonis, Nathan Wunderlich, Mark Greis, Kenneth D. Starczynowski, Daniel T. Volk, Andrew G. Blood Adv Myeloid Neoplasia Acute myeloid leukemia (AML) is an aggressive blood cancer that stems from the rapid expansion of immature leukemic blasts in the bone marrow. Mutations in epigenetic factors represent the largest category of genetic drivers of AML. The chromatin assembly factor CHAF1B is a master epigenetic regulator of transcription associated with self-renewal and the undifferentiated state of AML blasts. Upregulation of CHAF1B, as observed in almost all AML samples, promotes leukemic progression by repressing the transcription of differentiation factors and tumor suppressors. However, the specific factors regulated by CHAF1B and their contributions to leukemogenesis are unstudied. We analyzed RNA sequencing data from mouse MLL-AF9 leukemic cells and bone marrow aspirates, representing a diverse collection of pediatric AML samples and identified the E3 ubiquitin ligase TRIM13 as a target of CHAF1B-mediated transcriptional repression associated with leukemogenesis. We found that CHAF1B binds the promoter of TRIM13, resulting in its transcriptional repression. In turn, TRIM13 suppresses self-renewal of leukemic cells by promoting pernicious entry into the cell cycle through its nuclear localization and catalytic ubiquitination of cell cycle–promoting protein, CCNA1. Overexpression of TRIM13 initially prompted a proliferative burst in AML cells, which was followed by exhaustion, whereas loss of total TRIM13 or deletion of its catalytic domain enhanced leukemogenesis in AML cell lines and patient-derived xenografts. These data suggest that CHAF1B promotes leukemic development, in part, by repressing TRIM13 expression and that this relationship is necessary for leukemic progression. The American Society of Hematology 2023-05-22 /pmc/articles/PMC10469560/ /pubmed/37205848 http://dx.doi.org/10.1182/bloodadvances.2022009438 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 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 Myeloid Neoplasia
Dean, Sarai T.
Ishikawa, Chiharu
Zhu, Xiaoqin
Walulik, Sean
Nixon, Timothy
Jordan, Jessica K.
Henderson, Samantha
Wyder, Michael
Salomonis, Nathan
Wunderlich, Mark
Greis, Kenneth D.
Starczynowski, Daniel T.
Volk, Andrew G.
Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development
title Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development
title_full Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development
title_fullStr Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development
title_full_unstemmed Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development
title_short Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development
title_sort repression of trim13 by chromatin assembly factor chaf1b is critical for aml development
topic Myeloid Neoplasia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10469560/
https://www.ncbi.nlm.nih.gov/pubmed/37205848
http://dx.doi.org/10.1182/bloodadvances.2022009438
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