Enhanced natural-killer cell and erythropoietic activities in VEGF-A-overexpressing mice delay F-MuLV-induced erythroleukemia.
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 with wild-type controls. These results suggested an altered physiologic 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 (ie, CD34+, CD36+, and Ter119+ cells) were evident in the bone marrow, spleen, and peripheral blood of Vegfhi/+ mice. The CFU-E levels were significantly elevated 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 natural killer (NK) cell activity account for the extended survival of erythroleukemic, Vegfhi/+ mice.
Cervi
David
D
Department of Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Shaked
Yuval
Y
Haeri
Mehran
M
Usenko
Tatiana
T
Lee
Christina R
CR
Haigh
Jody J
JJ
Nagy
Andras
A
Kerbel
Robert S
RS
Yefenof
Eitan
E
Ben-David
Yaacov
Y
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D015672:Erythroid Precursor Cells; D004920:Erythropoiesis / Q000187:drug effects; D005622:Friend murine leukemia virus / Q000502:physiology*; D015870:Gene Expression; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2