Long non-coding RNAs in hematopoiesis and blood malignancy

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 DESCRIPTION (provided by applicant): Recent efforts to functionally annotate the human genome have revealed that up to 75% 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 long non-coding RNA. By generating high depth RNA-Seq datasets integrated with chromatin features, our lab and others have revealed the presence of many thousands of previously un-annotated lncRNAs, 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 in human cancer. We provide here, using a combination of deep transcriptome sequencing, high-resolution transcription factor occupancy mapping and chromatin interaction data, the first comprehensive identification and characterization of lncRNA expression and function in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic malignancy driven by oncogenic NOTCH1 transcriptional activity. Moreover, we provide the first map of oncogene (NOTCH1)-targeted lncRNAs in this tumor and identify an individual lncRNA (called LUNAR1) that appears to be essential for tumor growth as it controls cytokine (IGF1) signaling. These studies suggest that: a) lncRNAs could be used as both biomarkers and therapy targets in human cancer (see AIM1), b) more efficient methods for large-scale inference and validation of lncRNA function are needed to fully understand their biological significance (see AIM2) and, c) LUNAR1 is one of the first lncRNAs that can control growth of acute leukemia and a potential therapeutic target (see AIM3). In this application we address in detail all these important issues and attempt to directly connect lncRNA deregulation to leukemia initiation and progression.