The fps/fes proto-oncogene regulates hematopoietic lineage output.
OBJECTIVE
The fps/fes proto-oncogene is abundantly expressed in myeloid cells, and the Fps/Fes cytoplasmic protein-tyrosine kinase is implicated in signaling downstream from hematopoietic cytokines, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (EPO). Studies using leukemic cell lines have previously suggested that Fps/Fes contributes to granulomonocytic differentiation, and that it might play a more selective role in promoting survival and differentiation along the monocytic pathway. In this study we have used a genetic approach to explore the role of Fps/Fes in hematopoiesis.


METHODS
We used transgenic mice that tissue-specifically express a mutant human fps/fes transgene (fps(MF)) that was engineered to encode Fps/Fes kinase that is activated through N-terminal myristoylation (MFps). Hematopoietic function was assessed using lineage analysis, hematopoietic progenitor cell colony-forming assays, and biochemical approaches.


RESULTS
fps(MF) transgenic mice displayed a skewed hematopoietic output reflected by increased numbers of circulating granulocytic and monocytic cells and a corresponding decrease in lymphoid cells. Bone marrow colony assays of progenitor cells revealed a significant increase in the number of both granulomonocytic and multi-lineage progenitors. A molecular analysis of signaling in mature monocytic cells showed that MFps promoted GM-CSF-induced STAT3, STAT5, and ERK1/2 activation.


CONCLUSIONS
These observations support a role for Fps/Fes in signaling pathways that contribute to lineage determination at the level of multi-lineage hematopoietic progenitors as well as the more committed granulomonocytic progenitors.
Sangrar
Waheed
W
Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario, K7L 3N6, Canada.
Gao
Yan
Y
Zirngibl
Ralph A
RA
Scott
Michelle L
ML
Greer
Peter A
PA
D000818:Animals; D001773:Blood Cells / Q000166:cytology; D002452:Cell Count; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D004951:Esterification; D015681:Fusion Proteins, gag-onc / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D038042:Myelopoiesis; D015202:Protein Engineering; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D019076:Transgenes
D015681:Fusion Proteins, gag-onc; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011505:Protein-Tyrosine Kinases; C068415:v-fps oncogene protein, Fujinami sarcoma virus