Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

Koen Debackere, Lukas Marcelis, Sofie Demeyer, Marlies Vanden Bempt, Nicole Mentens, Olga Gielen, Kris Jacobs, Michael Broux, Gregor Verhoef, Lucienne Michaux, Carlos Graux, Iwona Wlodarska, Philippe Gaulard, Laurence Leval, Thomas Tousseyn, Jan Cools () and Daan Dierickx ()
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Koen Debackere: Laboratory for Experimental Hematology, KU Leuven
Lukas Marcelis: Translational Cell & Tissue Research, KU Leuven
Sofie Demeyer: Center for Cancer Biology, VIB
Marlies Vanden Bempt: Laboratory for Experimental Hematology, KU Leuven
Nicole Mentens: Center for Cancer Biology, VIB
Olga Gielen: Center for Cancer Biology, VIB
Kris Jacobs: Center for Cancer Biology, VIB
Michael Broux: Center for Cancer Biology, VIB
Gregor Verhoef: Laboratory for Experimental Hematology, KU Leuven
Lucienne Michaux: Center for Human Genetics, KU Leuven
Carlos Graux: Mont-Godinne University Hospital
Iwona Wlodarska: Center for Human Genetics, KU Leuven
Philippe Gaulard: Département de Pathologie, Groupe Hospitalier Henri Mondor, AP-HP
Laurence Leval: Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University
Thomas Tousseyn: Translational Cell & Tissue Research, KU Leuven
Jan Cools: Center for Cancer Biology, VIB
Daan Dierickx: Laboratory for Experimental Hematology, KU Leuven

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24037-4

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