Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity

Diamond-Blackfan anemia is a bone marrow failure syndrome associated with heterozygous mutations in the ribosomal protein S19 (RPS19) gene in a subgroup of patients. One of the interacting partners with RPS19 is the oncoprotein PIM-1 kinase. We intercrossed Rps19 (+/-) and Pim-1 (-/-) mice strains to study the effect from the disruption of both genes. The double mutant (Rps19 (+/-) Pim-1 (-/-) ) mice display normal growth with increased peripheral white and red blood cell counts when compared to the w.t. mice (Rps19 (+/+) Pim-1 (+/+) ). Molecular analysis of bone marrow cells in Rps19 (+/-) Pim-1 (-/-) mice revealed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl(2), Bcl(XL), and Mcl-1. This is associated with a reduction of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21. Our findings suggest that combined Rps19 insufficiency and Pim-1 deficiency promote murine myeloid cell growth through a deregulation of c-Myc and a simultaneous up-regulation of anti-apoptotic Bcl proteins.