Fiche publication
Date publication
août 2014
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROLLAND Delphine
Tous les auteurs :
Kiel MJ, Velusamy T, Rolland D, Sahasrabuddhe AA, Chung F, Bailey NG, Schrader A, Li B, Li JZ, Ozel AB, Betz BL, Miranda RN, Medeiros LJ, Zhao L, Herling M, Lim MS, Elenitoba-Johnson KS
Lien Pubmed
Résumé
The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5, and targeted pharmacologic inhibition of STAT5 with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.
Mots clés
Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Ataxia Telangiectasia Mutated Proteins, genetics, Base Sequence, Cell Death, drug effects, Cohort Studies, Computer Simulation, DNA Copy Number Variations, DNA Mutational Analysis, DNA, Neoplasm, genetics, Exome, Female, Humans, Interleukin Receptor Common gamma Subunit, genetics, Janus Kinase 1, genetics, Janus Kinase 3, chemistry, Leukemia, Prolymphocytic, T-Cell, drug therapy, Male, Middle Aged, Models, Molecular, Molecular Sequence Data, Mutation, Pimozide, pharmacology, Protein Conformation, STAT5 Transcription Factor, antagonists & inhibitors, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Tumor Cells, Cultured
Référence
Blood. 2014 Aug 28;124(9):1460-72
