Combined Disruptions of the Ribosomal Protein s19 and Pim1 Kinase Genes Are Associated with Increased Myeloid/Erythroid Cellularity and Reduced Apoptosis

Diamond Blackfan anemia (DBA) is characterized by reduced proliferation and increased apoptosis of erythroid progenitors. Approximately 25% of patients are heterozygous for mutations in the gene encoding ribosomal protein S19 (RPS19). The molecular mechanisms behind DBA remain unclear and RPS19 was recently shown to interact with PIM1 kinase. To elucidate the phenotypic and cellular effects of this interaction we generated mice strains with the genotypes Rps19 +/− Pim1 +/+; Rps19 +/+ Pim1 −/− and Rps19 +/− Pim1 −/−. We analyzed the mice for peripheral blood and bone marrow parameters as well as apoptotic markers in primary bone marrow cells. The double mutant mice (Rps19 +/− Pim1 −/−) show normal growth and life span with increased white and red blood cell counts when compared to wild type, Rps19 heterozygous, and Pim1 null mice, respectively. Analysis of proteins in bone marrow cells shows that the combination of Rps19 insufficiency and Pim1 deficiency is associated with increased levels of Stat5 as well as the anti-apoptotic markers Mcl-1, Bcl-2 and Bcl-XL. The pro-apoptotic markers Bak, Caspase-3 and p21 show decreased levels whereas p53 remains unchanged. These findings suggest a co-operative effect of Rps19 insufficiency and Pim1 deficiency on cell proliferation in murine hematopoiesis.