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Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia
Aldehyde dehydrogenases (ALDH) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of cases of T-cell acute lymphoblastic leukemia (T-ALL). However, its molecular function and role in the pathogenesis of T-ALL are largely unk...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168519/ https://www.ncbi.nlm.nih.gov/pubmed/32414855 http://dx.doi.org/10.3324/haematol.2019.245639 |
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author | Zhang, Chujing Amanda, Stella Wang, Cheng Tan, Tze King Ali, Muhammad Zulfaqar Leong, Wei Zhong Ng, Ley Moy Kitajima, Shojiro Li, Zhenhua Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi |
author_facet | Zhang, Chujing Amanda, Stella Wang, Cheng Tan, Tze King Ali, Muhammad Zulfaqar Leong, Wei Zhong Ng, Ley Moy Kitajima, Shojiro Li, Zhenhua Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi |
author_sort | Zhang, Chujing |
collection | PubMed |
description | Aldehyde dehydrogenases (ALDH) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of cases of T-cell acute lymphoblastic leukemia (T-ALL). However, its molecular function and role in the pathogenesis of T-ALL are largely unknown. Chromatin immunoprecipitation-sequencing and RNA-sequencing analyses showed that the oncogenic transcription factor TAL1 and its regulatory partners bind to the intronic regulatory element of the ALDH1A2 gene, directly inducing a T-ALL-specific isoform with enzymatic activity. ALDH1A2 was preferentially expressed in the TAL1-positive T-ALL subgroup. In TALL cell lines, depletion of ALDH1A2 inhibited cell viability and induced apoptosis. Interestingly, gene expression and metabolomic profiling revealed that ALDH1A2 supported glycolysis and the tricarboxylic acid cycle, accompanied by NADH production, by affecting multiple metabolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species, while the levels were reduced by ALDH1A2 overexpression both in vitro and in vivo. Overexpression of ALDH1A2 accelerated tumor onset and increased tumor penetrance in a zebrafish model of T-ALL. Taken together, our results indicate that ALDH1A2 protects against intracellular stress and promotes T-ALL cell metabolism and survival. ALDH1A2 overexpression enables leukemic clones to sustain a hyper-proliferative state driven by oncogenes. |
format | Online Article Text |
id | pubmed-8168519 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-81685192021-06-11 Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia Zhang, Chujing Amanda, Stella Wang, Cheng Tan, Tze King Ali, Muhammad Zulfaqar Leong, Wei Zhong Ng, Ley Moy Kitajima, Shojiro Li, Zhenhua Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi Haematologica Article Aldehyde dehydrogenases (ALDH) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of cases of T-cell acute lymphoblastic leukemia (T-ALL). However, its molecular function and role in the pathogenesis of T-ALL are largely unknown. Chromatin immunoprecipitation-sequencing and RNA-sequencing analyses showed that the oncogenic transcription factor TAL1 and its regulatory partners bind to the intronic regulatory element of the ALDH1A2 gene, directly inducing a T-ALL-specific isoform with enzymatic activity. ALDH1A2 was preferentially expressed in the TAL1-positive T-ALL subgroup. In TALL cell lines, depletion of ALDH1A2 inhibited cell viability and induced apoptosis. Interestingly, gene expression and metabolomic profiling revealed that ALDH1A2 supported glycolysis and the tricarboxylic acid cycle, accompanied by NADH production, by affecting multiple metabolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species, while the levels were reduced by ALDH1A2 overexpression both in vitro and in vivo. Overexpression of ALDH1A2 accelerated tumor onset and increased tumor penetrance in a zebrafish model of T-ALL. Taken together, our results indicate that ALDH1A2 protects against intracellular stress and promotes T-ALL cell metabolism and survival. ALDH1A2 overexpression enables leukemic clones to sustain a hyper-proliferative state driven by oncogenes. Fondazione Ferrata Storti 2020-05-15 /pmc/articles/PMC8168519/ /pubmed/32414855 http://dx.doi.org/10.3324/haematol.2019.245639 Text en Copyright© 2021 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Zhang, Chujing Amanda, Stella Wang, Cheng Tan, Tze King Ali, Muhammad Zulfaqar Leong, Wei Zhong Ng, Ley Moy Kitajima, Shojiro Li, Zhenhua Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia |
title | Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia |
title_full | Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia |
title_fullStr | Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia |
title_full_unstemmed | Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia |
title_short | Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia |
title_sort | oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of t-cell acute lymphoblastic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168519/ https://www.ncbi.nlm.nih.gov/pubmed/32414855 http://dx.doi.org/10.3324/haematol.2019.245639 |
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