ECTOPIC EXPRESSION OF MURINE TPO RECEPTOR (C-MPL) IN MICE IS PATHOGENIC AND INDUCES ERYTHROBLASTIC PROLIFERATION

c-mpl, the cellular homologue of the v-mpl oncogene transduced in the myeloproliferative leukemia virus (MPLV), encodes the receptor for thr ombopoietin, a cytokine involved in the proliferation and differentiat ion of cells of the megakaryocytic lineage. Here, we show that a retro virus containing murine c-mpl cDNA (HSFmmpl) is pathogenic in vivo whe n inoculated in adult mice. All mice developed hepatosplenomegaly and died within 9 to 12 weeks after infection. Histological analysis showe d that spleen, liver, and peripheral blood were invaded by erythroblas ts at every stage of differentiation. In contrast to the myeloprolifer ative syndrome induced by MPLV, we did not observe an infiltration of these organs with cells from the granulocytic lineage nor a thrombocyt osis. In fact, the platelet count of HSFmmpl mice progressively decrea sed and a severe thrombocytopenia was observed late in the course of t he disease, Further characterization of the target progenitor of HSFmm pl virus in the spleen and bone marrow of diseased animals was accompl ished using in vitro clonogenic progenitor cell assays. This analysis indicated that both late and early erythroid compartment (colony-formi ng unit-erythroid and burst-forming unit-erythroid) were largely incre ased in the spleens. The colony-forming unit-granulocyte-macrophage co mpartment was also increased but to a lesser extent, This study shows for the first time that ectopic expression of a member of the cytokine receptor superfamily promotes hematopoietic progenitor cell prolifera tion and could play a role in leukemogenesis. (C) 1996 by The American Society of Hematology.