Submitted November 10, 2005
Accepted October 10, 2006
Enhanced natural killer cell and erythropoietic activities in VEGF-A-overexpressing mice delay F-MuLV-induced erythroleukemia
David Cervi, Yuval Shaked, Mehran Haeri, Tatiana Usenko, Christina R Lee, Jody J Haigh, Andras Nagy, Robert S Kerbel, Eitan Yefenof, and Yaacov Ben-David*
Sunnybrook Health Sciences Centre, Canada
Flanders Interuniversity Institute for Biotechnology (FIB), Ghent University, Belgium
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Canada
Lautenberg Center of Immunology, Hadassah Medical School, Israel
* Corresponding author; email: bendavid{at}sri.utoronto.ca.
We have previously reported that VEGF-A, in combination with MCP-5, contributes to leukemia progression within the splenic microenvironment of mice infected with F-MuLV. To study the influence of constitutively elevated VEGF-A levels on the progression of erythroleukemia, mice heterozygous for a VEGF-A "hypermorphic" allele (VEGFhi/+) were inoculated with F-MuLV. Unexpectedly, a significant delay in erythroleukemia was observed in VEGFhi/+ mice when compared to wild-type controls. These results suggested an altered physiological response arising from elevated VEGF-A levels that decelerated erythroleukemic progression. Characterization of hematopoiesis in VEGFhi/+ spleens showed a higher natural killer cell activity, elevated B-cells and a decrease in T-cell number. Furthermore, higher erythroid progenitors; i.e., CD34+, CD36+ and Ter119+ cells were evident in the bone marrow, spleen and peripheral blood of VEGFhi/+ mice. The CFU-E counts were significantly increased in VEGFhi/+ bone-marrow cultures and this elevation was blocked by a neutralizing antibody to VEGF-A receptor (VEGFR-2). Moreover, erythroleukemic mice were treated with recombinant erythropoietin and similar to diseased VEGFhi/+ mice, showed a delay in disease progression. We propose that a compensatory erythropoietic response combined with increased NK cell activity account for the extended survival of erythroleukemic, VEGFhi/+ mice.
