Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783297363525238784 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5795782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT leongweizhong arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT tanshihao arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT ngocphuongcaothi arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT amandastella arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT yamaliceweiyee arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT liauweisiang arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT gongzhiyuan arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT lawtonleen arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT tenendanielg arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis AT sandatakaomi arid5basacriticaldownstreamtargetofthetal1complexthatactivatestheoncogenictranscriptionalprogramandpromotestcellleukemogenesis |