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The anemic Friend virus gp55 envelope protein induces erythroid differentiation in fetal liver colony-forming
S N Constantinescu1, H Wu, X Liu
1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Abstract:
The gp55 envelope proteins of the spleen focus-forming virus initiate erythroleukemia in adult mice. Because the gp55 from the polycythemic strain (gp55-P), but not from the anemic strain (gp55-A), activates the erythropoietin receptor (EpoR) for proliferation of hematopoietic cell lines, the mechanism by which gp55-A initiates erythroleukemia has remained a mystery. We show here that gp55-A activates the EpoR in fetal liver cells. In contrast to previous studies using bone marrow cells from phenylhydrazine-treated, anemic mice, we find that both gp55-A and gp55-P induce erythroid differentiation from colony-forming unit-erythroid (CFU-E) progenitors in fetal liver cells. The effects on CFU-Es of both gp55-A and -P are mediated by the EpoR, because no colonies are seen upon expression of either gp55 in EpoR-/- fetal liver cells. However, only gp55-P induces erythroid bursts from burst-forming unit-erythroid progenitors and only gp55-P induces Epo independence in Epo-dependent cell lines. Using chimeric gp55 P/A proteins, we extend earlier work showing that the transmembrane sequence determines the capacity of gp55 proteins to differentially activate EpoR signaling. We discuss the possibilities for different signaling capacities of gp55-A and -P in fetal liver and bone marrow-derived erythroid progenitor cells.
Insights
The spleen focus-forming virus gp55-A protein initiates erythroleukemia by activating the erythropoietin receptor (EpoR) in fetal liver cells, unlike previous findings. Both gp55-A and gp55-P induce erythroid differentiation in CFU-Es.
Area of Science:
- Molecular Biology
- Virology
- Hematopoiesis
Background:
- Spleen focus-forming virus (SFFV) gp55 envelope proteins cause erythroleukemia.
- gp55 from polycythemic strain (gp55-P) activates erythropoietin receptor (EpoR), but gp55 from anemic strain (gp55-A) does not, leaving the mechanism of gp55-A-induced leukemia unknown.
Purpose of the Study:
- To investigate the mechanism by which gp55-A initiates erythroleukemia.
- To compare the EpoR activation and downstream effects of gp55-A and gp55-P in different erythroid progenitor cells.
Main Methods:
- Expression of gp55-A and gp55-P in fetal liver cells and EpoR-/- fetal liver cells.
- Analysis of erythroid differentiation and proliferation from colony-forming unit-erythroid (CFU-E) and burst-forming unit-erythroid (BFU-E) progenitors.
- Use of chimeric gp55 P/A proteins to study the role of the transmembrane sequence.
Main Results:
- Both gp55-A and gp55-P activate EpoR and induce erythroid differentiation in CFU-Es from fetal liver cells.
- Only gp55-P induces erythroid bursts from BFU-Es and Epo independence in Epo-dependent cell lines.
- The transmembrane sequence of gp55 determines its differential EpoR signaling capacity.
Conclusions:
- gp55-A can activate EpoR in fetal liver cells, contributing to erythroleukemia initiation.
- Differential activation of EpoR by gp55-A and gp55-P is mediated by their transmembrane sequences.
- Distinct signaling capacities of gp55 variants in fetal liver versus bone marrow-derived erythroid progenitors warrant further investigation.