A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q(−) syndrome

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed our understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for the human 5q(−) syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74 – Nid67 interval (containing the Ribosomal protein S14 gene – Rps14) causes macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. This is associated with defective bone marrow progenitor development, increased apoptosis and the appearance of bone marrow cells expressing high levels of p53. Notably, intercrossing with p53-deficient mice, completely rescues the progenitor cell defect, restoring CMP/MEP, GMP and HSC bone marrow populations. This novel mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q(−) syndrome.