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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...

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Autores principales: Lim, Fang Qi, Chan, Allison Si-Yu, Yokomori, Rui, Huang, Xiao Zi, Theardy, Madelaine Skolastika, Yeoh, Allen Eng Juh, Tan, Shi Hao, Sanda, Takaomi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
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.
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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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