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

Shi Hao Tan, Wei Zhong Leong, Phuong Cao Thi Ngoc, Tze King Tan, Fatima Carla Bertulfo, Mei Chee Lim, Omer An, Zhenhua Li, Allen Eng Juh Yeoh, Melissa J. Fullwood, Daniel G. Tenen and Takaomi Sanda

Key Points

  • ARIEL functions as an enhancer RNA to mediate the chromatin-chromatin interaction between the ARID5B enhancer and promoter in T-ALL cells.

  • ARIEL plays an oncogenic role by activating the oncogenic transcriptional program in TAL1-positive T-ALL cells.

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.

  • Submitted September 11, 2018.
  • Revision received May 7, 2019.
  • Accepted May 7, 2019.