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ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis

The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich intera...

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Autores principales: Leong, Wei Zhong, Tan, Shi Hao, Ngoc, Phuong Cao Thi, Amanda, Stella, Yam, Alice Wei Yee, Liau, Wei-Siang, Gong, Zhiyuan, Lawton, Lee N., Tenen, Daniel G., Sanda, Takaomi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795782/
https://www.ncbi.nlm.nih.gov/pubmed/29326336
http://dx.doi.org/10.1101/gad.302646.117
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author Leong, Wei Zhong
Tan, Shi Hao
Ngoc, Phuong Cao Thi
Amanda, Stella
Yam, Alice Wei Yee
Liau, Wei-Siang
Gong, Zhiyuan
Lawton, Lee N.
Tenen, Daniel G.
Sanda, Takaomi
author_facet Leong, Wei Zhong
Tan, Shi Hao
Ngoc, Phuong Cao Thi
Amanda, Stella
Yam, Alice Wei Yee
Liau, Wei-Siang
Gong, Zhiyuan
Lawton, Lee N.
Tenen, Daniel G.
Sanda, Takaomi
author_sort Leong, Wei Zhong
collection PubMed
description The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2–4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active transcription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. ARID5B positively regulates the expression of TAL1 and its regulatory partners. ARID5B also activates the expression of the oncogene MYC. Importantly, ARID5B is required for the survival and growth of T-ALL cells, and forced expression of ARID5B in immature thymocytes results in thymus retention, differentiation arrest, radioresistance, and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the TAL1-induced regulatory circuit and MYC in T-ALL, thereby contributing to T-cell leukemogenesis.
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spelling pubmed-57957822018-06-01 ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis Leong, Wei Zhong Tan, Shi Hao Ngoc, Phuong Cao Thi Amanda, Stella Yam, Alice Wei Yee Liau, Wei-Siang Gong, Zhiyuan Lawton, Lee N. Tenen, Daniel G. Sanda, Takaomi Genes Dev Research Paper The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2–4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active transcription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. ARID5B positively regulates the expression of TAL1 and its regulatory partners. ARID5B also activates the expression of the oncogene MYC. Importantly, ARID5B is required for the survival and growth of T-ALL cells, and forced expression of ARID5B in immature thymocytes results in thymus retention, differentiation arrest, radioresistance, and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the TAL1-induced regulatory circuit and MYC in T-ALL, thereby contributing to T-cell leukemogenesis. Cold Spring Harbor Laboratory Press 2017-12-01 /pmc/articles/PMC5795782/ /pubmed/29326336 http://dx.doi.org/10.1101/gad.302646.117 Text en © 2018 Leong et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Leong, Wei Zhong
Tan, Shi Hao
Ngoc, Phuong Cao Thi
Amanda, Stella
Yam, Alice Wei Yee
Liau, Wei-Siang
Gong, Zhiyuan
Lawton, Lee N.
Tenen, Daniel G.
Sanda, Takaomi
ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
title ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
title_full ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
title_fullStr ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
title_full_unstemmed ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
title_short ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
title_sort arid5b as a critical downstream target of the tal1 complex that activates the oncogenic transcriptional program and promotes t-cell leukemogenesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795782/
https://www.ncbi.nlm.nih.gov/pubmed/29326336
http://dx.doi.org/10.1101/gad.302646.117
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