title: Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade.
abstract: 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.
authors.affiliation: Inserm (EMI 351), Faculté de Médecine, Université de Picardie J. Verne, Amiens, France.
authors.forename: Noria
authors.initials: N
authors.lastname: Harir
authors.forename: Cédric
authors.initials: C
authors.lastname: Boudot
authors.forename: Katrin
authors.initials: K
authors.lastname: Friedbichler
authors.forename: Karoline
authors.initials: K
authors.lastname: Sonneck
authors.forename: Rudin
authors.initials: R
authors.lastname: Kondo
authors.forename: Séverine
authors.initials: S
authors.lastname: Martin-Lannerée
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.forename: Marc
authors.initials: M
authors.lastname: Kerenyi
authors.forename: Saliha
authors.initials: S
authors.lastname: Yahiaoui
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.forename: Jean
authors.initials: J
authors.lastname: Gondry
authors.forename: Laurence
authors.initials: L
authors.lastname: Bénit
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusanter-Fourt
authors.forename: Kaïss
authors.initials: K
authors.lastname: Lassoued
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gouilleux
mesh_terms: 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*
chemical_list: D050799:STAT5 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt