Craven, S.E., French, D., Ye, W., de Sauvage, F., and Rosenthal, A. (2005) Loss of hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndromes. Blood. 105(9):3528-3534.
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.