FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome.
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.
Yamada
Yoshiyuki
Y
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA.
Sanchez-Aguilera
Abel
A
Brandt
Eric B
EB
McBride
Melissa
M
Al-Moamen
Nabeel J H
NJ
Finkelman
Fred D
FD
Williams
David A
DA
Cancelas
Jose A
JA
Rothenberg
Marc E
ME
D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D017681:Hypereosinophilic Syndrome / Q000209:etiology*; D034721:Mastocytosis, Systemic / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects*; D019089:Stem Cell Factor / Q000502:physiology*; D039221:mRNA Cleavage and Polyadenylation Factors / Q000627:therapeutic use*
C479818:FIP1L1 protein, human; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D039221:mRNA Cleavage and Polyadenylation Factors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt