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Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia
T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. In this study, we performed chemical scr...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890034/ https://www.ncbi.nlm.nih.gov/pubmed/36073513 http://dx.doi.org/10.3324/haematol.2022.280761 |
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author | Lim, Fang Qi Chan, Allison Si-Yu Yokomori, Rui Huang, Xiao Zi Theardy, Madelaine Skolastika Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi |
author_facet | Lim, Fang Qi Chan, Allison Si-Yu Yokomori, Rui Huang, Xiao Zi Theardy, Madelaine Skolastika Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi |
author_sort | Lim, Fang Qi |
collection | PubMed |
description | T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. In this study, we performed chemical screening to identify small molecules that can inhibit the enhancer activity driven by TAL1 using the GIMAP enhancer reporter system. Among approximately 3,000 compounds, PIK-75, a known inhibitor of PI3K and CDK, was found to strongly inhibit the enhancer activity. Mechanistic analysis demonstrated that PIK-75 blocks transcriptional activity, which primarily affects TAL1 target genes as well as AKT activity. TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL. |
format | Online Article Text |
id | pubmed-9890034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-98900342023-02-13 Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia Lim, Fang Qi Chan, Allison Si-Yu Yokomori, Rui Huang, Xiao Zi Theardy, Madelaine Skolastika Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi Haematologica Article - Acute Lymphoblastic Leukemia T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. In this study, we performed chemical screening to identify small molecules that can inhibit the enhancer activity driven by TAL1 using the GIMAP enhancer reporter system. Among approximately 3,000 compounds, PIK-75, a known inhibitor of PI3K and CDK, was found to strongly inhibit the enhancer activity. Mechanistic analysis demonstrated that PIK-75 blocks transcriptional activity, which primarily affects TAL1 target genes as well as AKT activity. TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL. Fondazione Ferrata Storti 2022-09-08 /pmc/articles/PMC9890034/ /pubmed/36073513 http://dx.doi.org/10.3324/haematol.2022.280761 Text en Copyright© 2023 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 - Acute Lymphoblastic Leukemia Lim, Fang Qi Chan, Allison Si-Yu Yokomori, Rui Huang, Xiao Zi Theardy, Madelaine Skolastika Yeoh, Allen Eng Juh Tan, Shi Hao Sanda, Takaomi Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia |
title | Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia |
title_full | Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia |
title_fullStr | Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia |
title_full_unstemmed | Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia |
title_short | Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia |
title_sort | targeting dual oncogenic machineries driven by tal1 and pi3k-akt pathways in t-cell acute lymphoblastic leukemia |
topic | Article - Acute Lymphoblastic Leukemia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890034/ https://www.ncbi.nlm.nih.gov/pubmed/36073513 http://dx.doi.org/10.3324/haematol.2022.280761 |
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