Abstract IA24: Regulation of acute leukemia initiation and progression by long noncoding RNAs.

Abstract

Abstract Recent efforts to functionally annotate the human genome have revealed that up to 70% of our DNA is transcriptionally active. Since a very small portion of our genome encodes proteins many have hypothesized that a portion of this pervasive transcription results in production of non-coding RNA. By generating high depth RNA-Seq datasets integrated with chromatin features, several labs have revealed the presence of many thousands of previously un-annotated long non-coding RNAs (lncRNA), which are dynamically expressed in response to various stimuli in diverse cellular contexts. Despite these compelling advances, the vast majority of putative lncRNAs have not been proven to be functionally important, although a small portion have clearly been shown to play key regulatory roles. Most importantly, very little is known on the biological role of lncRNAs for human disease and specifically cancer. We provide here, using a combination of deep transcriptome sequencing, high-resolution transcription factor occupancy mapping and chromosome conformation capture data, the first comprehensive identification and characterization of lncRNA expression and function in T-cell acute lymphoblastic leukemia, an aggressive hematologic malignancy affecting both children and adults, driven by oncogenic NOTCH1 mutations and transcriptional activation. Moreover, we provide the first map of oncogene (NOTCH1)-targeted lncRNAs in this disease and identify an individual lncRNA (called LUNAR1) that appears to be essential for tumor growth as it controls cytokine (IGF1) signaling. Indeed, we were able to show that the LUNAR1 locus loops on a novel IGF1R enhancer controlling the expression of this important cytokine receptor. These studies suggest that: a) lncRNAs could be used as both biomarkers and therapy targets in human cancer, b) more efficient methods for large-scale inference and validation of lncRNA function are needed to fully understand their biological significance and, c) LUNAR1 is one of the first lncRNAs that can control growth of acute leukemia and a potential therapeutic target. These points will be addressed in this presentation. Citation Format: Iannis Aifantis. Regulation of acute leukemia initiation and progression by long noncoding RNAs. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA24.