title: Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia.
abstract: The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Durinck
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Van Loocke
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van der Meulen
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Van de Walle
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Ongenaert
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Rondou
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Wallaert
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: C E
authors.initials: CE
authors.lastname: de Bock
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Poppe
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: J
authors.initials: J
authors.lastname: Cools
authors.affiliation: Genome Rearrangements and Cancer Laboratory, U944 INSERM, University Paris Diderot and Hematology Laboratory, Saint-Louis Hospital, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Center for Medical Genetics, Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Van Vlierberghe
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D009857:Oncogenes; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; C497761:NOTCH1 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; C071250:TLX1 protein, human