title: β-Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1.
abstract: Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of β-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of β-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of β-Catenin in these T-ALL cells and demonstrate that the MYC 3' enhancer required β-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1.
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Gekas
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: T
authors.initials: T
authors.lastname: D'Altri
authors.affiliation: Department of Cell Biology, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Aligué
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: González
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Espinosa
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Bigas
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; C538949:PKF115-584; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D051176:beta Catenin; D010569:Perylene