title: The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium; kaat.durinck@ugent.be franki.speleman@ugent.be.
authors.forename: Kaat
authors.initials: K
authors.lastname: Durinck
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Annelynn
authors.initials: A
authors.lastname: Wallaert
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium;
authors.forename: Inge
authors.initials: I
authors.lastname: Van de Walle
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Wouter
authors.initials: W
authors.lastname: Van Loocke
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: Volders
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Suzanne
authors.initials: S
authors.lastname: Vanhauwaert
authors.affiliation: Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium;
authors.forename: Ellen
authors.initials: E
authors.lastname: Geerdens
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Genome Rearrangements and Cancer Laboratory, U944 INSERM, University Paris Diderot and Hematology Laboratory, Saint-Louis Hospital, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium;
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium;
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium;
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium; kaat.durinck@ugent.be franki.speleman@ugent.be.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases