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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3528-3534. Prepublished online as a Blood First Edition Paper on January 13, 2005; DOI 10.1182/blood-2004-03-1089. This Article Full Text (PDF) All Versions of this Article: 2004-03-1089v1 105/9/3528    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Craven, S. E Articles by Rosenthal, A. Search for Related Content PubMed PubMed Citation Articles by Craven, S. E Articles by Rosenthal, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 22, 2004 Accepted January 6, 2005 Loss of hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndromes Sarah E Craven*, Dorothy French, Weilan Ye, Frederic de Sauvage, and Arnon Rosenthal Department of Molecular Biology, Genentech Inc., South San Francisco, CA, USA Pathology Department, Genentech Inc., South San Francisco, CA, USA Rinat Neuroscience, Palo Alto, CA, USA * Corresponding author; email: craven{at}gene.com. The myelodysplastic syndromes (MDS) are a heterogeneous group of often fatal hematopoietic stem cell disorders for which neither curative nor standard treatment exists. The complex karyotypes and multi-step nature of MDS have severely restricted the identification of causative genetic mutations and thus limited insight into new and more effective therapies. Here we describe a zebrafish mutant crimsonless (crs) with a developmental blood defect that closely recapitulates the ineffective hematopoiesis of MDS including anemia, dysplasia, increased blood cell apoptosis, and multi-lineage cytopenia. By positional cloning, rescue, and morpholino knockdown experiments, we demonstrate that crs encodes a conserved mitochondrial matrix chaperone HSPA9B containing a glycine-to-glutamate substitution within the substrate binding domain. This mutation compromises mitochondrial function, producing oxidative stress and apoptosis distinctly in blood cells. Thus we identify an essential role for hspa9b in hematopoiesis and implicate both loss of HSPA9B specifically and mitochondrial dysfunction generally in the pathogenesis of MDS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. J. Weiss and C. O. dos Santos Chaperoning erythropoiesis Blood, March 5, 2009; 113(10): 2136 - 2144. [Abstract] [Full Text] [PDF] A. Elorza, B. Hyde, H. K. Mikkola, S. Collins, and O. S. Shirihai UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis J. Biol. Chem., November 7, 2008; 283(45): 30461 - 30470. [Abstract] [Full Text] [PDF] V. G. Sankaran, S. H. Orkin,, and C. R. Walkley Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis Genes & Dev., February 15, 2008; 22(4): 463 - 475. [Abstract] [Full Text] [PDF]

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