JAK/STAT3 signaling pathway is often deregulated in hematopoietic disorders including peripheral T-cell lymphoma. We describe two novel mechanisms leading to the constitutive activation of STAT3 in ALK- ALCL. Oncogenic JAK1 or STAT3 mutations are associated to hyperactive pSTAT3 that regulated canonical STAT3 and ATF3 genes. Moreover, synergizing JAK1 and STAT3 mutants sustain the neoplastic growth, which can be efficiently controlled in vitro and in an ALCL patient derived tumorgraft model by JAK1/2 inhibitors. We have discovered that novel chimera, displaying concomitant transcriptional and kinase activities, are power oncogenes capable to sustain via STAT3 the ALCL phenotype and can be uniquely neutralized by a novel ROS1 inhibitor. The pharmacological inhibition of JAK/STAT3 represents a novel strategy for the treatment of molecular stratified ALCL.

Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

ACQUAVIVA, ANDREA;FICARRA, ELISA;
2015

Abstract

JAK/STAT3 signaling pathway is often deregulated in hematopoietic disorders including peripheral T-cell lymphoma. We describe two novel mechanisms leading to the constitutive activation of STAT3 in ALK- ALCL. Oncogenic JAK1 or STAT3 mutations are associated to hyperactive pSTAT3 that regulated canonical STAT3 and ATF3 genes. Moreover, synergizing JAK1 and STAT3 mutants sustain the neoplastic growth, which can be efficiently controlled in vitro and in an ALCL patient derived tumorgraft model by JAK1/2 inhibitors. We have discovered that novel chimera, displaying concomitant transcriptional and kinase activities, are power oncogenes capable to sustain via STAT3 the ALCL phenotype and can be uniquely neutralized by a novel ROS1 inhibitor. The pharmacological inhibition of JAK/STAT3 represents a novel strategy for the treatment of molecular stratified ALCL.
Ramona Crescenzo; Francesco Abate; Elena Lasorsa; Fabrizio Tabbo’; Marcello Gaudiano; Nicoletta Chiesa; Filomena Di Giacomo; Elisa Spaccarotella; Luigi Barbarossa; Elisabetta Ercole; Maria Todaro; Michela Boi; ACQUAVIVA, ANDREA; FICARRA, ELISA; Domenico Novero; Andrea Rinaldi; Thomas Tousseyn; Andreas Rosenwald; Lukas Kenner; Lorenzo Cerroni; Alexander Tzankov; Maurilio Ponzoni; Marco Paulli; Dennis Weisenburger; Wing C. Chan; Javeed Iqbal; Miguel A. Piris; Alberto Zamo’; Carmela Ciardullo; Davide Rossi; Gianluca Gaidano; Stefano Pileri; Enrico Tiacci; Brunangelo Falini; Leonard D. Shultz; Laurence Mevellec; Jorge E. Vialard; Roberto Piva; Francesco Bertoni; Raul Rabadan; Giorgio Inghirami
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/878323
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