Autocrine stimulation by erythropoietin in transgenic mice results in erythroid proliferation without neoplastic transformation

Blood Cells, Molecules & Diseases
A MadanP T Curtin

Abstract

Erythropoietin (Epo) autocrine stimulation has been implicated in erythroleukemia. To develop a model of Epo autocrine stimulation, we made transgenic mice using a construct that linked the human Epo gene to an erythroid-specific regulatory element, designated 5'HS-2, from the human beta-globin locus control region. We hypothesized that Epo gene expression would be targeted to erythroid cells in these mice, resulting in autocrine stimulation of erythroid progenitor cell growth in culture, and that chronic autocrine Epo stimulation would result in erythroleukemia. Transgenic mice containing intact copies of the 5'HS-2Epo construction had elevated hematocrits, reticulocyte counts and serum Epo levels and marked splenic enlargement. Analysis of RNA isolated from organs of transgenic mice revealed constitutive Epo mRNA expression primarily in spleen, blood and bone marrow. RNA samples from anemic transgenic mice revealed Epo gene induction only in the liver. Marrow derived from 5'HS-2Epo mice grew BFU-E in the absence of exogenous Epo. Despite observation of up to 2 years, no mouse developed erythroleukemia, demonstrating that Epo autocrine stimulation alone is insufficient for progression to malignancy. These studies show that 5'H...Continue Reading

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Related Concepts

Cell Division Phases
Neoplastic Cell Transformation
Erythropoietin
Mice, Inbred Strains
Founder Mice, Transgenic
Episomes
Poly(A) Tail
Erythroid Progenitor Cells
Gene Expression

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