No 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 IntroductionMast cells (MCs) are critical effector cells in innate and acquired immunity. 1,2 Under various circumstances and pathologic conditions, MCs increase in number and accumulate in various tissues and organs. In many cases, reactive MC hyperplasia is found. 1 However, MCs (MC progenitors) may also undergo neoplastic transformation. 3,4 Disorders that lead to enhanced proliferation and/or accumulation of neoplastic MCs are well defined by WHO criteria. [3][4][5][6] MCs are derived from pluripotent hematopoietic cells in the bone marrow and undergo terminal maturation in their ultimate tissue destinations under the influence of stem cell factor, also known as Kit ligand. [7][8][9] Studies in MC-deficient mouse strains displaying mutations in the stem cell factor (SCF) gene or the gene encoding the SCF receptor, c-Kit, as well as activating c-Kit mutations that are considered to represent major transforming hits in mastocytosis, underline the importance of SCF and Kit for MC development. [10][11][12][13][14][15][16] Binding of SCF to Kit induces activation of various signaling molecules including phospholipase C, the Src family tyrosine kinase, the scaffolding molecule Gab2, the MAP Kinases Erk1/2, the JAK tyrosine kinase, the Phosphatidyl-inositol 3-kinase (PI3K), and the Stat transcription factors. [17][18][19] Lessons from gene deletion studies in mice have indicated that PI3K, Gab2, and Stat5 play a critical role in MC development and function, suggesting that these molecules may represent important downstream effectors of c-Kit signaling. [20][21][22] Moreover, recent data have shown that Stat5 and Gab2 are also required for signaling via the high affinity IgE receptor Fc⑀RI that plays a critical role in MC function and allergic response. 23,24 Besides their physiologic role in MCs, accumulating evidence suggests that persistent Stat5 and PI3K activation is frequently found in hematopoietic neoplasms and solid tumors. 25,26 It has also been described that disease-related oncogenic tyrosine kinases like Tel-Jak2, Bcr-Abl, Tel-PDGFR␤, mutated Kit or Flt3 receptors, and the Jak2 (V617F) mutant, detectable in most myeloproliferative disorders (MPDs), induce constitutive activation of Stat5, PI3K and its downstream effector, the serine threonine kinase Akt. [27][28][29][30][31][32][33][34][35] Moreover, Stat5 proteins were found to be required for Tel-Jak2-and Bcr-Abl-induc...