| Title | Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Crescenzo R, Abate F, Lasorsa E, Tabbo' F, Gaudiano M, Chiesa N, Di Giacomo F, Spaccarotella E, Barbarossa L, Ercole E, Todaro M, Boi M, Acquaviva A, Ficarra E, Novero D, Rinaldi A, Tousseyn T, Rosenwald A, Kenner L, Cerroni L, Tzankov A, Ponzoni M, Paulli M, Weisenburger D, Chan WC, Iqbal J, Piris MA, Zamo' A, Ciardullo C, Rossi D, Gaidano G, Pileri S, Tiacci E, Falini B, Shultz LD, Mevellec L, Vialard JE, Piva R, Bertoni F, Rabadan R, Inghirami G |
| Corporate Authors | European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies” |
| Journal | Cancer Cell |
| Volume | 27 |
| Issue | 4 |
| Pagination | 516-32 |
| Date Published | 2015 Apr 13 |
| ISSN | 1878-3686 |
| Keywords | Activating Transcription Factor 3, Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Janus Kinase 1, Lymphoma, Large-Cell, Anaplastic, Mice, Mutant Chimeric Proteins, NF-kappa B, Phosphorylation, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Signal Transduction, STAT3 Transcription Factor, TYK2 Kinase |
| Abstract | A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo. |
| DOI | 10.1016/j.ccell.2015.03.006 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 25873174 |
| PubMed Central ID | PMC5898430 |
| Grant List | R01 CA179044 / CA / NCI NIH HHS / United States R01 CA185486 / CA / NCI NIH HHS / United States U54 CA121852 / CA / NCI NIH HHS / United States R01CA185486 / CA / NCI NIH HHS / United States |
Related Faculty:
Giorgio Inghirami, M.D.