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(American Journal of Pathology. 1998;153:247-254.)
© 1998 American Society for Investigative Pathology

Regular Articles

Association of v-Ha-ras Transgene Expression with Development of Erythroleukemia in Tg.AC Transgenic Mice

Carol S. Trempus* , Sandra Ward , Georgia Farris , David Malarkey , Randall S. Faircloth* , Ronald E. Cannon* and Joel F. Mahler

From the Laboratory of Environmental Carcinogenesis and Mutagenesis* and the Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, and the Chemical Industrial Institute of Toxicology, Research Triangle Park, North Carolina

A transgenic mouse line (Tg.AC) carrying an activated v-Ha-ras oncogene fused to the embryonic -globin promoter develops an array of spontaneous epithelial and mesenchymal neoplasms. In this report we describe the morphological, immunophenotypic, and molecular features of a unique hematopoietic neoplasm in these mice. The cardinal lesion of this disease is marked hepatomegaly due to leukemic proliferation and infiltration. In the peripheral blood, there is a marked increase in the number of metarubricytes and other less differentiated erythroid progenitor cells. Leukemic cells stain positively with an erythroid-associated nuclear transcription factor (GATA-1). Using a reverse transcription polymerase chain reaction assay, co-expression of GATA-1 and endogenous -globin genes is detected in hematopoietic tissues of nonleukemic transgenic and nontransgenic mice. ras transgene expression is, however, detected only in normal bone marrow and leukemic tissues of transgenic 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 -globin promoter start site, supporting the belief that the -globin promoter directs v-Ha-ras expression in erythroid progenitor cells, ultimately leading to leukemic transformation.

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