title: Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9.
abstract: Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8--whose expression was increased in mutant erythroblasts, monocytes and macrophages--is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.affiliation: Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
authors.forename: Monica Ventura
authors.initials: MV
authors.lastname: Ferreira
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Cailin E
authors.initials: CE
authors.lastname: Joyce
authors.affiliation: Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Hartigan
authors.affiliation: Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Beier
authors.affiliation: Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Medicine I, University Hospital Carl Gustav Carus, University of Technology, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Büsche
authors.affiliation: Institute of Pathology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Knüchel
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Waters
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Chu
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Novina
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: R Coleman
authors.initials: RC
authors.lastname: Lindsley
authors.affiliation: Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000740:Anemia / Q000235:genetics* / Q000276:immunology; D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000473:pathology; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057895:Haploinsufficiency / Q000235:genetics*; D006412:Hematopoietic Stem Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008533:Megakaryocytes; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012269:Ribosomal Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D012269:Ribosomal Proteins; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D016159:Tumor Suppressor Protein p53; C039747:ribosomal protein S14