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Updated: Apr 26, 2026
Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia
Thomas Trimarchi1, Erhan Bilal2, Panagiotis Ntziachristos1
1Howard Hughes Medical Institute, Laura and Isaac Perlmutter Cancer Center, and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Abstract:
Notch signaling is a key developmental pathway that is subject to frequent genetic and epigenetic perturbations in many different human tumors. Here we investigate whether long noncoding RNA (lncRNA) genes, in addition to mRNAs, are key downstream targets of oncogenic Notch1 in human T cell acute lymphoblastic leukemia (T-ALL). By integrating transcriptome profiles with chromatin state maps, we have uncovered many previously unreported T-ALL-specific lncRNA genes, a fraction of which are directly controlled by the Notch1/Rpbjκ activator complex. Finally we have shown that one specific Notch-regulated lncRNA, LUNAR1, is required for efficient T-ALL growth in vitro and in vivo due to its ability to enhance IGF1R mRNA expression and sustain IGF1 signaling. These results confirm that lncRNAs are important downstream targets of the Notch signaling pathway, and additionally they are key regulators of the oncogenic state in T-ALL.
Insights
Long noncoding RNAs (lncRNAs) are downstream targets of oncogenic Notch1 signaling in T-cell acute lymphoblastic leukemia (T-ALL). A specific lncRNA, LUNAR1, drives T-ALL growth by enhancing IGF1R signaling.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Notch signaling is crucial in development and frequently altered in human cancers.
- Aberrant Notch1 signaling drives T-cell acute lymphoblastic leukemia (T-ALL) pathogenesis.
- The role of long noncoding RNAs (lncRNAs) as downstream targets of Notch signaling in T-ALL is not well understood.
Purpose of the Study:
- To investigate lncRNA genes as downstream targets of oncogenic Notch1 in T-ALL.
- To identify novel T-ALL-specific lncRNAs regulated by Notch1.
- To determine the functional role of Notch-regulated lncRNAs in T-ALL growth.
Main Methods:
- Integration of transcriptome profiling with chromatin state mapping.
- Analysis of Notch1/Rpbjκ direct transcriptional targets.
- In vitro and in vivo functional assays to assess T-ALL growth.
Main Results:
- Discovery of numerous T-ALL-specific lncRNA genes.
- Identification of lncRNAs directly controlled by the Notch1/Rpbjκ complex.
- Demonstration that LUNAR1, a Notch-regulated lncRNA, promotes T-ALL proliferation by upregulating IGF1R mRNA and sustaining IGF1 signaling.
Conclusions:
- lncRNAs are significant downstream targets of the Notch signaling pathway in T-ALL.
- Notch-regulated lncRNAs, such as LUNAR1, are critical regulators of the oncogenic state in T-ALL.
- Targeting lncRNAs may offer novel therapeutic strategies for T-ALL.
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