There is mounting evidence from the study of animal models of human disorders of defective ribosome biogenesis, including Diamond-Blackfan anemia and Treacher Collins syndrome, that ribosomal stress leads to activation of the p53 pathway. 1-3 Stabilization of p53 leads to cell-cycle arrest and apoptosis. We read with interest the manuscript by Danilova showing that deficiency of RPS19 in the zebrafish results in developmental abnormalities and defective erythropoiesis through the activation of the p53 protein family. 3 The 5q syndrome is the most distinct of all the myelodysplastic syndromes (MDS), and is defined under the World Health Organization (WHO) classification as refractory anemia with the del (5q) as the sole karyotypic abnormality [MDS with del (5q)]. 4, 5 We have recently generated a mouse model of the human 5q syndrome (with haploinsufficiency of RPS14) that shows the key features of the human disease, including a macrocytic anemia. 6 p53 is activated in this mouse model of the human 5q syndrome and intercrossing with p53-deficient mice completely rescued the progenitor cell defect. 6 We thus hypothesized that activation of p53 and of the p53 pathway may underlie the pathogenesis of the human 5q syndrome. Data from several laboratories suggests that up-regulation of the p53 pathway is a common response to haploinsufficiency of ribosomal proteins. We now present an analysis of the p53 pathway in the 5q syndrome; gene expression profiling (performed as previously described7 on Affymetrix U133 Plus2. 0 arrays) was used to compare

CD34 cells from 16 patients with 5q syndrome with CD34 cells from 17 healthy controls, and 1570 significantly differentially expressed genes (P. 05, Benjamini-Hochberg correction) were identified. We then imported this gene list into the DAVID gene ontology application, and the p53 pathway was returned as significantly deregulated (p. 031) in the 5q syndrome (Figure 1A). Ten genes in the p53 pathway were