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FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome.

Abstract
Expression of the fusion gene FIP1-like 1/platelet-derived growth factor receptor alpha (FIP1L1/PDGFRalpha, F/P) and dysregulated c-kit tyrosine kinase activity are associated with systemic mastocytosis (SM) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES). We analyzed SM development and pathogenesis in a murine CEL model induced by F/P in hematopoietic stem cells and progenitors (HSCs/Ps) and T-cell overexpression of IL-5 (F/P-positive CEL mice). These mice had more mast cell (MC) infiltration in the bone marrow (BM), spleen, skin, and small intestine than control mice that received a transplant of IL-5 transgenic HSCs/Ps. Moreover, intestinal MC infiltration induced by F/P expression was severely diminished, but not abolished, in mice injected with neutralizing anti-c-kit antibody, suggesting that endogenous stem cell factor (SCF)/c-kit interaction synergizes with F/P expression to induce SM. F/P-expressing BM HSCs/Ps showed proliferation and MC differentiation in vitro in the absence of cytokines. SCF stimulated greater migration of F/P-expressing MCs than mock vector-transduced MCs. F/P-expressing bone marrow-derived mast cells (BMMCs) survived longer than mock vector control BMMCs in cytokine-deprived conditions. The increased proliferation and survival correlated with increased SCF-induced Akt activation. In summary, F/P synergistically promotes MC development, activation, and survival in vivo and in vitro in response to SCF.
AuthorsYoshiyuki Yamada, Abel Sanchez-Aguilera, Eric B Brandt, Melissa McBride, Nabeel J H Al-Moamen, Fred D Finkelman, David A Williams, Jose A Cancelas, Marc E Rothenberg
JournalBlood (Blood) Vol. 112 Issue 6 Pg. 2500-7 (Sep 15 2008) ISSN: 1528-0020 [Electronic] United States
PMID18539901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • FIP1L1 protein, human
  • Recombinant Fusion Proteins
  • Stem Cell Factor
  • mRNA Cleavage and Polyadenylation Factors
  • Receptor, Platelet-Derived Growth Factor alpha
  • Proto-Oncogene Proteins c-akt
Topics
  • Animals
  • Cell Differentiation
  • Cell Movement
  • Cell Proliferation
  • Disease Models, Animal
  • Hypereosinophilic Syndrome (etiology)
  • Mastocytosis, Systemic (chemically induced, etiology, pathology)
  • Mice
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Receptor, Platelet-Derived Growth Factor alpha (therapeutic use)
  • Recombinant Fusion Proteins (adverse effects)
  • Stem Cell Factor (physiology)
  • mRNA Cleavage and Polyadenylation Factors (therapeutic use)

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