Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade

Noria Harir , Cedric Boudot (1) , Katrin Friedbichler , Karoline Sonneck (2) , Rudin Kondo , Séverine Martin-Lannerée (3) , Lukas Kenner (4) , Marc Kerenyi , Saliha Yahiaoui (5) , Valérie Gouilleux-Gruart (6) , Jean Gondry (7) , Laurence Bénit (8) , Isabelle Dusanter-Fourt (8) , Kaiss Lassoued (5) , Peter Valent (2) , Richard Moriggl (9) , Fabrice Gouilleux (6)

1 Affectations Mineralisantes du Systeme Cardiovasculaire : Calcifications Arterielles et Valvulaires Aortiques
2 Medizinische Universität Wien = Medical University of Vienna
3 IJM (UMR_7592) - Institut Jacques Monod
4 BBVA Foundation - Cancer Cell Biology Programme
5 Développement normal et pathologique des lymphocytes et signalisation
6 GICC UMR 6239 CNRS - Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011]
7 TMCD2 - Transporteurs membranaires, chimioresistance et drug-design
8 IC UM3 (UMR 8104 / U1016) - Institut Cochin
9 Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria]

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 (cS5F) 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

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Cancer

Noria Harir, Cedric Boudot, Katrin Friedbichler, Karoline Sonneck, Rudin Kondo, et al.. Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade. Blood, 2008, 112 (6), pp.2463-2473. ⟨10.1182/blood-2007-09-115477⟩. ⟨hal-02424605⟩