Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes.

Autor:	Zambetti NA; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Bindels EM; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Van Strien PM; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Valkhof MG; 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., Adisty MN; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Hoogenboezem RM; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Sanders MA; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Rommens JM; 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., Touw IP; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands., Raaijmakers MH; Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands m.h.g.raaijmakers@erasmusmc.nl.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2015 Oct; Vol. 100 (10), pp. 1285-93. Date of Electronic Publication: 2015 Jul 16.
DOI:	10.3324/haematol.2015.131573
Abstrakt:	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. (Copyright© Ferrata Storti Foundation.)
Databáze:	MEDLINE
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