The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia
Autor: | Kaat Durinck, Annelynn Wallaert, Inge Van de Walle, Wouter Van Loocke, Pieter-Jan Volders, Suzanne Vanhauwaert, Ellen Geerdens, Yves Benoit, Nadine Van Roy, Bruce Poppe, Jean Soulier, Jan Cools, Pieter Mestdagh, Jo Vandesompele, Pieter Rondou, Pieter Van Vlierberghe, Tom Taghon, Frank Speleman |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: | |
Zdroj: | Haematologica, Vol 99, Iss 12 (2014) |
Druh dokumentu: | article |
ISSN: | 0390-6078 1592-8721 |
DOI: | 10.3324/haematol.2014.115683 |
Popis: | 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. |
Databáze: | Directory of Open Access Journals |
Externí odkaz: |