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Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation

Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a n...

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Autores principales: Mizuno, Hideaki, Koya, Junji, Masamoto, Yosuke, Kagoya, Yuki, Kurokawa, Mineo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486204/
https://www.ncbi.nlm.nih.gov/pubmed/34363719
http://dx.doi.org/10.1111/cas.15098
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author Mizuno, Hideaki
Koya, Junji
Masamoto, Yosuke
Kagoya, Yuki
Kurokawa, Mineo
author_facet Mizuno, Hideaki
Koya, Junji
Masamoto, Yosuke
Kagoya, Yuki
Kurokawa, Mineo
author_sort Mizuno, Hideaki
collection PubMed
description Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1‐driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1‐overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA‐mediated knockdown selectively decreased Evi1‐driven leukemogenesis in vitro. Moreover, pharmacological or shRNA‐mediated Fbp1 inhibition in secondarily transplanted Evi1‐overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.
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spelling pubmed-84862042021-10-07 Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation Mizuno, Hideaki Koya, Junji Masamoto, Yosuke Kagoya, Yuki Kurokawa, Mineo Cancer Sci Original Articles Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1‐driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1‐overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA‐mediated knockdown selectively decreased Evi1‐driven leukemogenesis in vitro. Moreover, pharmacological or shRNA‐mediated Fbp1 inhibition in secondarily transplanted Evi1‐overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML. John Wiley and Sons Inc. 2021-08-22 2021-10 /pmc/articles/PMC8486204/ /pubmed/34363719 http://dx.doi.org/10.1111/cas.15098 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Mizuno, Hideaki
Koya, Junji
Masamoto, Yosuke
Kagoya, Yuki
Kurokawa, Mineo
Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
title Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
title_full Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
title_fullStr Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
title_full_unstemmed Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
title_short Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
title_sort evi1 upregulates fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486204/
https://www.ncbi.nlm.nih.gov/pubmed/34363719
http://dx.doi.org/10.1111/cas.15098
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