ASSOCIATION OF V-HA-RAS TRANSGENE EXPRESSION WITH DEVELOPMENT OF ERYTHROLEUKEMIA IN TG.AC TRANSGENIC MICE

A transgenic mouse line (Tg,AC) carrying an activated v-Ha-ras oncogen e fused to the embryonic zeta-globin promoter develops an array of spo ntaneous epithelial and mesenchymal neoplasms. In this report we descr ibe the morphological, immunophenotypic, and molecular features of a u nique hematopoietic neoplasm in these mice. The cardinal lesion of thi s disease is marked hepatomegaly due to leukemic proliferation and inf iltration. In the peripheral blood, there is a marked increase in the number of metarubricytes and other less differentiated erythroid proge nitor cells. Leukemic cells stain positively with an erythroid-associa ted nuclear transcription factor (GATA-1), Using a reverse transcripti on polymerase chain reaction assay, co-expression of GATA-1 and endoge nous zeta-globin genes is detected in hematopoietic tissues of nonleuk emic transgenic and nontransgenic mice, ras transgene expression is, h owever, detected only in normal bone marrow and leukemic tissues of tr ansgenic mice, and 5' mapping experiments using S1 protection analysis of total RNA from leukemic tissue indicates that transcription of the transgene mRNA is initiated from the natural zeta-globin promoter sta rt site, supporting the belief that the zeta-globin promoter directs v -Ha-ras expression in erythroid progenitor cells, ultimately leading t o leukemic transformation.