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.
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Authors | Yoshiyuki 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 |
Journal | Blood
(Blood)
Vol. 112
Issue 6
Pg. 2500-7
(Sep 15 2008)
ISSN: 1528-0020 [Electronic] United States |
PMID | 18539901
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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