Harir Noria, Boudot Cédric, Friedbichler Katrin, Sonneck Karoline, Kondo Rudin, Martin-Lannerée Séverine, Kenner Lukas, Kerenyi Marc, Yahiaoui Saliha, Gouilleux-Gruart Valérie, Gondry Jean, Bénit Laurence, Dusanter-Fourt Isabelle, Lassoued Kaïss, Valent Peter, Moriggl Richard, Gouilleux Fabrice
Inserm (EMI 351), Faculté de Médecine, Université de Picardie J. Verne, Amiens, France.
Blood. 2008 Sep 15;112(6):2463-73. doi: 10.1182/blood-2007-09-115477. Epub 2008 Jun 25.
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.
Kit的D816V突变变体可触发多种信号通路，被认为是肥大细胞（MC）肿瘤发生恶性转化所必需的。我们在此描述，Stat5-PI3K-Akt级联的组成性激活控制着肿瘤性MC的发育。发现逆转录病毒转导的活性Stat5（cS5(F)）可触发PI3K和Akt激活，并将小鼠骨髓祖细胞转化为组织浸润性MC。肥大细胞增多症患者的原发性肿瘤性Kit D816V(+) MC也显示出激活的Stat5，发现其定位于细胞质，并与PI3K形成信号复合物，随后激活Akt。最后，Stat5或Akt活性的敲低导致肿瘤性Kit D816V(+) MC的生长受到抑制。这些数据表明，下游的Stat5-PI3K-Akt信号级联对于Kit D816V介导的肿瘤性MC的生长和存活至关重要。
