IN-VIVO ANALYSIS OF PIM-1 DEFICIENCY

The Pim-1 proto-oncogene encodes a highly conserved serine/threonine p hosphokinase (1 - 5) which is predominantly expressed in hematopoietic organs and gonads in mammals (6-9). Overexpression of Pim-1 predispos es to lymphomagenesis in mice (8, 1 0, 11). To develop a further under standing of Pim-1 in molecular terms, as well as in terms of its poten tial role in hematopoietic development, we have generated mice deficie nt in Pim-1 function. Pim-1-deficient mice are ostensibly normal, heal thy and fertile. Detailed comparative analyses of the hematopoietic sy stems of the mutant mice and their wild-type littermates showed that t hey are indistinguishable for most of the parameters studied. Our anal yses revealed one unexpected phenotype that correlated with the level of Pim-1 expression: Pim-1 deficiency correlated with a erythrocyte mi crocytosis, whereas overexpression of Pim-1 in E(mu)-Pim-1-transgenic mice resulted in erythrocyte macrocytosis. In order to confirm that th e observed decrease in erythrocyte Mean Cell Volume (MCV) was attribut able to the Pim-1 deficiency, we developed mice transgenic for a Pim-1 gene construct with its own promoter and showed that this transgene c ould restore the low erythrocyte Mean Cell Volume observed in the Pim- 1-deficient mice to near wild-type levels. These results might be rele vant to the observed involvement of the Pim-1 gene in mouse erythroleu kemogenesis (12). The surprising lack of a readily observed phenotype in the lymphoid compartment of the Pim-1-deficient mice, suggests a he retofore unrecognized degree of in vivo functional redundancy of this highly conserved proto-oncogene.