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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA194923-02
Application #
9063113
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2015-05-04
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Carroll, William L; Aifantis, Iannis; Raetz, Elizabeth (2017) Beating the Clock in T-cell Acute Lymphoblastic Leukemia. Clin Cancer Res 23:873-875
Lazaris, Charalampos; Kelly, Stephen; Ntziachristos, Panagiotis et al. (2017) HiC-bench: comprehensive and reproducible Hi-C data analysis designed for parameter exploration and benchmarking. BMC Genomics 18:22
Wang, Eric; Aifantis, Ioannis (2017) Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite. Cancer Discov 7:1065-1066
Cimmino, Luisa; Dolgalev, Igor; Wang, Yubao et al. (2017) Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell 170:1079-1095.e20
Cimmino, Luisa; Aifantis, Iannis (2017) Alternative roles for oxidized mCs and TETs. Curr Opin Genet Dev 42:1-7
Valls, Ester; Lobry, Camille; Geng, Huimin et al. (2017) BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells. Cancer Discov 7:506-521
Aranda-Orgilles, Beatriz; SaldaƱa-Meyer, Ricardo; Wang, Eric et al. (2016) MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis. Cell Stem Cell 19:784-799
Ntziachristos, Panagiotis; Abdel-Wahab, Omar; Aifantis, Iannis (2016) Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol 17:1016-24
Strikoudis, Alexandros; Lazaris, Charalampos; Trimarchi, Thomas et al. (2016) Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nat Cell Biol 18:1127-1138
Guillamot, Maria; Cimmino, Luisa; Aifantis, Iannis (2016) The Impact of DNA Methylation in Hematopoietic Malignancies. Trends Cancer 2:70-83

Showing the most recent 10 out of 15 publications