Journal
HAEMATOLOGICA
Volume 99, Issue 12, Pages 1808-1816Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2014.115683
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Funding
- Fund for Scientific Research Flanders ('FWO Vlaanderen') [G.0202.09, G.0869.10N, 3G055013N, 3G056413N, 3GA00113N, 3G065614, G.0C47.13N, G0B2913N, G037514N, 3G002711]
- IWT Vlaanderen
- Belgian Foundation against Cancer [SCIE 2010-177]
- Ghent University [01G01910]
- Cancer Plan from the Federal Public Service of Health
- Children Cancer Fund Ghent
- Belgian Program of Interuniversity Poles of Attraction [IUAP P7/03, P7/07]
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Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34(+) thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34(+) and Notch inactive CD4(+)CD8(+) thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia.
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