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.
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA.
Yoshiyuki
Y
Yamada
Abel
A
Sanchez-Aguilera
Eric B
EB
Brandt
Melissa
M
McBride
Nabeel J H
NJ
Al-Moamen
Fred D
FD
Finkelman
David A
DA
Williams
Jose A
JA
Cancelas
Marc E
ME
Rothenberg
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