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

Abstract

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