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 thrombopoietin, a cytokine involved in the proliferation and differentiation of cells of the megakaryocytic lineage. Here, we show that a retrovirus containing murine c-mpl cDNA (HSFmmpl) is pathogenic in vivo when inoculated in adult mice. All mice developed hepatosplenomegaly and died within 9 to 12 weeks after infection. Histological analysis showed that spleen, liver, and peripheral blood were invaded by erythroblasts at every stage of differentiation. In contrast to the myeloproliferative syndrome induced by MPLV, we did not observe an infiltration of these organs with cells from the granulocytic lineage nor a thrombocytosis. In fact, the platelet count of HSFmmpl mice progressively decreased and a severe thrombocytopenia was observed late in the course of the disease. Further characterization of the target progenitor of HSFmmpl virus in the spleen and bone marrow of diseased animals was accomplished using in vitro clonogenic progenitor cell assays. This analysis indicated that both late and early erythroid compartment (colony-forming unit-erythroid and burst-forming unit-erythroid) were largely increased in the spleens. The colony-forming unit-granulocyte-macrophage compartment 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 proliferation and could play a role in leukemogenesis.
Cocault
L
L
INSERM U 363, Institut Cochin de Génétique Moléculaire, Hôpital Cochin, Paris, France.
Bouscary
D
D
Le Bousse Kerdiles
C
C
Clay
D
D
Picard
F
F
Gisselbrecht
S
S
Souyri
M
M
D000818:Animals; D001483:Base Sequence; D001772:Blood Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D002999:Clone Cells / Q000473:pathology; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006251:Harvey murine sarcoma virus / Q000235:genetics; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000503:physiopathology; D009363:Neoplasm Proteins; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000633:toxicity*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology; D014162:Transfection
D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human