1. Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified
- Author
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Daan Dierickx, Philippe Gaulard, Carlos Graux, Koen Debackere, Laurence de Leval, Nicole Mentens, Jan Cools, Lucienne Michaux, Kris Jacobs, Thomas Tousseyn, Sofie Demeyer, Olga Gielen, Michaël Broux, Iwona Wlodarska, Marlies Vanden Bempt, Lukas Marcelis, Gregor Verhoef, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service d'hématologie
- Subjects
0301 basic medicine ,Oncogene Proteins, Fusion ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Proto-Oncogene Proteins c-fyn ,Cohort Studies ,Mice ,0302 clinical medicine ,RNA-Seq ,Receptor ,Cancer genetics ,Multidisciplinary ,Forkhead Box Protein O1 ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,RNA-Binding Proteins ,hemic and immune systems ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Sin3 Histone Deacetylase and Corepressor Complex ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,T-cell lymphoma ,Adaptor Proteins, Signal Transducing/genetics ,Adaptor Proteins, Signal Transducing/metabolism ,Animals ,Cell Line, Tumor ,Cell Membrane/metabolism ,DNA-Binding Proteins/genetics ,DNA-Binding Proteins/metabolism ,Forkhead Box Protein O1/genetics ,Forkhead Box Protein O1/metabolism ,Gene Expression Regulation, Neoplastic/genetics ,Humans ,Intracellular Signaling Peptides and Proteins/metabolism ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ,Lymphoma, T-Cell, Peripheral/genetics ,Lymphoma, T-Cell, Peripheral/metabolism ,Lymphoma, T-Cell, Peripheral/pathology ,Mice, Inbred C57BL ,NF-kappa B/metabolism ,Oncogene Proteins, Fusion/genetics ,Oncogene Proteins, Fusion/metabolism ,Proto-Oncogene Proteins c-fyn/genetics ,Proto-Oncogene Proteins c-fyn/metabolism ,RNA-Binding Proteins/genetics ,RNA-Binding Proteins/metabolism ,Receptors, Antigen, T-Cell/metabolism ,Signal Transduction/genetics ,Sin3 Histone Deacetylase and Corepressor Complex/genetics ,Sin3 Histone Deacetylase and Corepressor Complex/metabolism ,bcl-X Protein/antagonists & inhibitors ,bcl-X Protein/metabolism ,Signal transduction ,Signal Transduction ,Science ,T cell ,Receptors, Antigen, T-Cell ,bcl-X Protein ,Peripheral T-cell lymphoma not otherwise specified ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,FYN ,medicine ,Adaptor Proteins, Signal Transducing ,Cell Membrane ,T-cell receptor ,Lymphoma, T-Cell, Peripheral ,General Chemistry ,medicine.disease ,Lymphoma ,030104 developmental biology ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Cancer research ,Ex vivo - Abstract
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs., Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.
- Published
- 2021
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