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Blood. 2019 May 10. pii: blood.2018874503. doi: 10.1182/blood.2018874503. [Epub ahead of print]

The enhancer RNA ARIEL activates the oncogenic transcriptional program in T-cell acute lymphoblastic leukemia.

Author information

1
Cancer Science Institute, National University of Singapore, Singapore.
2
Cancer Science Institute of Singapore, National Univeristy of Singapore, Singapore.
3
Cancer Science Institute of Singapore, National University of Singapore, Sweden.
4
Cancer Science Institute of Singapore, National University of Singapore.
5
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
6
Duke-NUS Medical School, Singapore, Singapore.
7
Bioinformatics Core, Cancer Science Institute of Singapore, NUS, Singapore.
8
Paediatrics, National University of Singapore, Singapore.
9
Cancer Science Institute, Singapore.
10
Harvard Stem Cell Institute, United States.
11
Cancer Science Institute of Singapore, National University of Singapore, Singapore csitakao@nus.edu.sg.

Abstract

The oncogenic transcription factor TAL1 regulates the transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL). ARID5B is one of critical downstream targets of TAL1 which further activates the oncogenic regulatory circuit in T-ALL cells. Here, we elucidated the molecular functions of the non-coding RNA, ARID5B Inducing Enhancer Associated Long non-coding RNA (ARIEL), in T-ALL pathogenesis. We demonstrated that ARIEL is specifically activated in TAL1-positive T-ALL cases, and its expression is associated with ARID5B enhancer activity. ARIEL recruits mediator proteins to the ARID5B enhancer, promotes enhancer-promoter interactions, and activates the expression of ARID5B, thereby positively regulating the TAL1-induced transcriptional program and the MYC oncogene. The TAL1 complex coordinately regulates the expression of ARIEL. Knockdown of ARIEL inhibits cell growth and survival of T-ALL cells in culture and blocks disease progression in a murine xenograft model. Our results indicate that ARIEL plays an oncogenic role as an enhancer RNA in T-ALL.

PMID:
31076442
DOI:
10.1182/blood.2018874503

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