title: Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes.
abstract: Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome.
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Noemi A
authors.initials: NA
authors.lastname: Zambetti
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Eric M J
authors.initials: EM
authors.lastname: Bindels
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Paulina M H
authors.initials: PM
authors.lastname: Van Strien
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands Current address: Laboratory for Cell Therapy, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.
authors.forename: Marijke G
authors.initials: MG
authors.lastname: Valkhof
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Adisty
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Remco M
authors.initials: RM
authors.lastname: Hoogenboezem
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Program in Genetics & Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto, ON, Canada.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands m.h.g.raaijmakers@erasmusmc.nl.
authors.forename: Marc H G P
authors.initials: MH
authors.lastname: Raaijmakers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001855:Bone Marrow Diseases / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D004195:Disease Models, Animal; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics; D017353:Gene Deletion; D006410:Hematopoiesis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008068:Lipomatosis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism*; D009503:Neutropenia / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D000081003:Shwachman-Diamond Syndrome; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D011506:Proteins; C513661:Sbds protein, mouse; D016159:Tumor Suppressor Protein p53