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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4627-4634.
Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-08-3115.
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HEMATOPOIESIS
Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia
Johan Flygare,
Thomas Kiefer,
Koichi Miyake,
Taiju Utsugisawa,
Isao Hamaguchi,
Lydie Da Costa,
Johan Richter,
Edward J. Davey,
Hans Matsson,
Niklas Dahl,
Maciej Wiznerowicz,
Didier Trono, and
Stefan Karlsson
From the Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and The Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden; the Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan; the Hôpital Bicêtre, Le Kremlin-Bicêtre, France; the Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University Hospital, Uppsala, Sweden; the Department of Genetics and Microbiology, University of Geneva, Geneva, Switzerland; and the Clinic for Internal Medicine C, Department of Hematology and Oncology, Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany.
Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34+ umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34+ CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34+ cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development. (Blood. 2005;105: 4627-4634)
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