title: Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia.
abstract: Calcium ions (Ca(2+)) function as universal second messengers in eukaryotic cells, including immune cells. Ca(2+) is crucial for peripheral T-lymphocyte activation and effector functions, and influences thymocyte selection and motility in the developing thymus. However, the role of Ca(2+) signalling in early T-lymphocyte development is not well understood. Here we show that the inositol triphosphate receptors (IP3Rs) Ca(2+) ion channels are required for proliferation, survival and developmental progression of T-lymphocyte precursors. Our studies indicate that signalling via IP3Rs represses Sox13, an antagonist of the developmentally important transcription factor Tcf-1. In the absence of IP3R-mediated Ca(2+) signalling, repression of key Notch transcriptional targets--including Hes1--fail to occur in post β-selection thymocytes, and mice develop aggressive T-cell malignancies that resemble human T-cell acute lymphoblastic leukemia (T-ALL). These data indicate that IP3R-mediated Ca(2+) signalling reinforces Tcf-1 activity to both ensure normal development and prevent thymocyte neoplasia.
authors.affiliation: 1] Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.affiliation: Skaggs School of Pharmacy, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Leandro Gomez-Amaro
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Stachura
authors.affiliation: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Huayuan
authors.initials: H
authors.lastname: Tang
authors.affiliation: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Traver
authors.affiliation: Skaggs School of Pharmacy, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000072056:Transcription Factor HES-1
chemical_list: D001324:Autoantigens; D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C496488:Hnf1a protein, mouse; C110455:Sox13 protein, mouse