title: SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells.
abstract: The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self-renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co-expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network described here may be relevant to a majority of human T-ALL.
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Tremblay
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Tremblay
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Shanti
authors.initials: S
authors.lastname: Rojas-Sutterlin
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada.
authors.forename: Sabine
authors.initials: S
authors.lastname: Herblot
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Maisonneuve-Rosemont Hospital. Montreal, Quebec, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Maisonneuve-Rosemont Hospital. Montreal, Quebec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: Clinical Research Institute of Montreal (IRCM), Montreal, Quebec, Canada; Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Lécuyer
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Diogo F T
authors.initials: DF
authors.lastname: Veiga
authors.affiliation: Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Trang
authors.initials: T
authors.lastname: Hoang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D065150:Cellular Reprogramming; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D060168:Thymocytes / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D060588:LIM Domain Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C513044:Lmo1 protein, mouse; C490130:Lyl1 protein, mouse; C497762:Notch1 protein, mouse; C489366:Tal1 protein, mouse