Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade.
The D816V-mutated variant of Kit triggers multiple signaling pathways and is considered essential for malignant transformation in mast cell (MC) neoplasms. We here describe that constitutive activation of the Stat5-PI3K-Akt-cascade controls neoplastic MC development. Retrovirally transduced active Stat5 (cS5(F)) was found to trigger PI3K and Akt activation, and to transform murine bone marrow progenitors into tissue-infiltrating MCs. Primary neoplastic Kit D816V(+) MCs in patients with mastocytosis also displayed activated Stat5, which was found to localize to the cytoplasm and to form a signaling complex with PI3K, with consecutive Akt activation. Finally, the knock-down of either Stat5 or Akt activity resulted in growth inhibition of neoplastic Kit D816V(+) MCs. These data suggest that a downstream Stat5-PI3K-Akt signaling cascade is essential for Kit D816V-mediated growth and survival of neoplastic MCs.
Harir
Noria
N
Inserm (EMI 351), Faculté de Médecine, Université de Picardie J. Verne, Amiens, France.
Boudot
Cédric
C
Friedbichler
Katrin
K
Sonneck
Karoline
K
Kondo
Rudin
R
Martin-Lannerée
Séverine
S
Kenner
Lukas
L
Kerenyi
Marc
M
Yahiaoui
Saliha
S
Gouilleux-Gruart
Valérie
V
Gondry
Jean
J
Bénit
Laurence
L
Dusanter-Fourt
Isabelle
I
Lassoued
Kaïss
K
Valent
Peter
P
Moriggl
Richard
R
Gouilleux
Fabrice
F
D000818:Animals; D001854:Bone Marrow Cells; D016022:Case-Control Studies; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells; D006801:Humans; D017254:Leukemic Infiltration; D020935:MAP Kinase Signaling System; D034721:Mastocytosis, Systemic / Q000473:pathology*; D051379:Mice; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*
D050799:STAT5 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt