Abstract
NOTCH-regulated long noncoding RNAs (lncRNA) including LUNAR1 promote T-ALL cell growth.
Major finding: NOTCH-regulated long noncoding RNAs (lncRNA) including LUNAR1 promote T-ALL cell growth.
Mechanism: LUNAR1 enhances T-ALL growth via cis activation of IGF1R expression and IGF1 signaling.
Impact: lncRNAs regulate tumor maintenance and may serve as biomarkers or therapeutic targets.
Malignant transformation of T-lymphocyte progenitors results in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive disease that is frequently associated with activating mutations in NOTCH1 and exhibits a high mortality rate. Although genetic and epigenetic changes and the role of microRNAs have been characterized in T-ALL, the contribution of long noncoding RNAs (lncRNA), which lack protein-coding potential but may enhance the expression of neighboring genes, has yet to be studied. Trimarchi and colleagues combined ultra–high-depth RNA-sequencing and genome-wide chromatin state mapping to generate an all-inclusive lncRNA expression map in T-ALL. This analysis demonstrated tissue-specific expression of lncRNAs in T-ALL and normal T cells and identified previously uncharacterized T-ALL–specific lncRNAs. Additionally, examination of lncRNA promoters revealed enrichment of the NOTCH1/recombination signal binding protein for immunoglobulin κ J region (RBPJκ) transcriptional activator complex, suggesting that oncogenic NOTCH signaling may directly regulate the expression of a subset of lncRNAs. Indeed, NOTCH1 inhibition identified a NOTCH-dependent T-ALL lncRNA expression program that was differentially expressed in primary human NOTCH1-mutant T-ALLs compared with normal T cells. Leukemia-induced noncoding activator RNA 1 (LUNAR1), a NOTCH-regulated lncRNA, was highly expressed in T-ALL, in particular in T-ALL samples harboring NOTCH1 mutations, and was downregulated in response to NOTCH inhibition. LUNAR1 expression was regulated by an active NOTCH1-occupied enhancer in the nearby insulin-like growth factor1 receptor (IGF1R) gene. Furthermore, depletion of LUNAR1 reduced expression of IGF1R and IGF1 signaling and diminished T-ALL tumor growth. LUNAR1 functioned as an important component of the IGF1R enhancer and activated IGF1R expression in cis by recruiting the Mediator complex and RNA polymerase II to the IGF1R enhancer. These results identify LUNAR1 as a positive regulator of T-ALL cell growth and suggest lncRNAs as potential therapeutic targets for leukemia.
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