sbds expression and localization at the mitotic spindle in human myeloid progenitors作为表达和定位在人类骨髓祖细胞的有丝分裂纺锤体.pdfVIP

SBDS Expression and Localization at the Mitotic Spindle in Human Myeloid Progenitors 1 1 1 1 1,2 Claudia Orelio *, Paul Verkuijlen , Judy Geissler , Timo K. van den Berg , Taco W. Kuijpers 1 Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam, The Netherlands, 2 Emma Children’s Hospital, University of Amsterdam, Academic Medical Centre (AMC), Amsterdam, The Netherlands Abstract Background: Shwachman-Diamond Syndrome (SDS) is a hereditary disease caused by mutations in the SBDS gene. SDS is clinically characterized by pancreatic insufficiency, skeletal abnormalities and bone marrow dysfunction. The hematologic abnormalities include neutropenia, neutrophil chemotaxis defects, and an increased risk of developing Acute Myeloid Leukemia (AML). Although several studies have suggested that SBDS as a protein plays a role in ribosome processing/ maturation, its impact on human neutrophil development and function remains to be clarified. Methodology/Principal Findings: We observed that SBDS RNA and protein are expressed in the human myeloid leukemia PLB-985 cell line and in human hematopoietic progenitor cells by quantitative RT-PCR and Western blot analysis. SBDS expression is downregulated during neutrophil differentiation. Additionally, we observed that the differentiation and proliferation capacity of SDS-patient bone marrow hematopoietic progenitor cells in a liquid differentiation system was reduced as compared to control cultures. Immunofluorescence analysis showed that SBDS co-localizes with the mitotic spindle and in vitro binding studies reveal a direct interaction of SBDS with microtubules. In interphase cells a perinuclear