title: The LMO2 oncogene regulates DNA replication in hematopoietic cells.
abstract: Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7; Molecular Biology Program, University of Montreal, Montreal, QC, Canada H1T 2M4;
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Sincennes
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors.forename: Magali
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors.forename: Benoît
authors.initials: B
authors.lastname: Grondin
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7; Molecular Biology Program, University of Montreal, Montreal, QC, Canada H1T 2M4;
authors.forename: Véronique
authors.initials: V
authors.lastname: Lisi
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors.forename: Diogo F T
authors.initials: DF
authors.lastname: Veiga
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors.forename: André
authors.initials: A
authors.lastname: Haman
authors.affiliation: Cancer Research Center of Toulouse, Toulouse 31024, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montreal, Montreal, QC, Canada H1T 2M4;
authors.forename: Nazar
authors.initials: N
authors.lastname: Mashtalir
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montreal, Montreal, QC, Canada H1T 2M4;
authors.forename: El Bachir
authors.initials: el B
authors.lastname: Affar
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7; Molecular Biology Program, University of Montreal, Montreal, QC, Canada H1T 2M4; Departments of Pharmacology and Biochemistry, University of Montreal, Montreal, QC, Canada H3T 1J2.
authors.forename: Alain
authors.initials: A
authors.lastname: Verreault
authors.affiliation: Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7; Molecular Biology Program, University of Montreal, Montreal, QC, Canada H1T 2M4; Departments of Pharmacology and Biochemistry, University of Montreal, Montreal, QC, Canada H3T 1J2 trang.hoang@umontreal.ca.
authors.forename: Trang
authors.initials: T
authors.lastname: Hoang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D004261:DNA Replication / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics*; D051379:Mice; D018741:Replication Origin; D016196:S Phase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C513188:Lmo2 protein, mouse
keywords: DNA replication; LMO2; T-cell acute lymphoblastic leukemia; cell cycle; hematopoietic cells