FER and FES tyrosine kinase fusions in follicular T-cell lymphoma

Debackere, Koen; Krogt, Jo-Anne van der; Tousseyn, Thomas; Ferreiro, Julio Antonio Finalet; Roosbroeck, Katrien Van; Graux, Carlos; Dierickx, Daan; Ameye, Geneviève; Vandenberghe, Peter; Marcelis, Lukas; Cools, Jan; Włodarska, Iwona

doi:10.1182/blood.2019002401

Cited by 20 publications

(11 citation statements)

References 24 publications

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“…To identify fusion events in PTCL-NOS, we performed high coverage, paired-end RNA sequencing (RNA-seq) on a cohort of 15 PTCL-NOS (Supplementary Table 1 ) cases and 3 PTCL-TFH 13 . Gene expression analysis indicated expression of T follicular helper (T fh ) markers in the PTCL-TFH cases (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…Different isoforms, including zeta, theta, and iota, are overexpressed in PTCLs (52,70). They may promote cell survival through higher nitric oxide synthase (NOS) activity, which may represent a suitable target (71). Recently, Debackere et al described t (1, 5)(p34;q21.3) and t (15, 16)(q26.1;q22.1) with ITK-FER and RLTPR-FES rearrangements, both acting through STAT3 phosphorylation (72).…”

Section: Other Tyrosine Kinases In Ptclsmentioning

confidence: 99%

Tyrosine kinases in nodal peripheral T-cell lymphomas

Piccaluga

Cascianelli²,

Inghirami

2023

Front. Oncol.

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Nodal peripheral T-cell lymphomas (PTCL) are uncommon and heterogeneous tumors characterized by a dismal prognosis. Targeted therapy has been proposed. However, reliable targets are mostly represented by a few surface antigens (e.g., CD52 and CD30), chemokine receptors (e.g., CCR4), and epigenetic gene expression regulation. In the last two decades, however, several studies have supported the idea that tyrosine kinase (TK) deregulation might be relevant for both the pathogenesis and treatment of PTCL. Indeed, they can be expressed or activated as a consequence of their involvement in genetic lesions, such as translocations, or by ligand overexpression. The most striking example is ALK in anaplastic large-cell lymphomas (ALCL). ALK activity is necessary to support cell proliferation and survival, and its inhibition leads to cell death. Notably, STAT3 was found to be the main downstream ALK effector. Other TKs are consistently expressed and active in PTCLs, such as PDGFRA, and members of the T-cell receptor signaling family, such as SYK. Notably, as in the case of ALK, STAT proteins have emerged as key downstream factors for most of the involved TK.

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“…This fusion acts as a constitutively active SYK tyrosine kinase and drives lymphomagenesis by triggering antigen-independent activation of TCR signaling. Translocations involving FER and FES have been recently described, including ITK-FER and RLTPR-FES , that result in the activation of the STAT3 signaling ( 88 ).…”

Section: Nodal T-follicular Helper Cell Lymphomasmentioning

confidence: 99%

Pathologic and molecular insights in nodal T-follicular helper cell lymphomas

2023

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T-follicular helper (TFH) cells are one of the T-cell subsets with a critical role in the regulation of germinal center (GC) reactions. TFH cells contribute to the positive selection of GC B-cells and promote plasma cell differentiation and antibody production. TFH cells express a unique phenotype characterized by PD-1hi, ICOShi, CD40Lhi, CD95hi, CTLAhi, CCR7lo, and CXCR5hi. Three main subtypes of nodal TFH lymphomas have been described: 1) angioimmunoblastic-type, 2) follicular-type, and 3) not otherwise specified (NOS). The diagnosis of these neoplasms can be challenging, and it is rendered based on a combination of clinical, laboratory, histopathologic, immunophenotypic, and molecular findings. The markers most frequently used to identify a TFH immunophenotype in paraffin-embedded tissue sections include PD-1, CXCL13, CXCR5, ICOS, BCL6, and CD10. These neoplasms feature a characteristic and similar, but not identical, mutational landscape with mutations in epigenetic modifiers (TET2, DNMT3A, IDH2), RHOA, and T-cell receptor signaling genes. Here, we briefly review the biology of TFH cells and present a summary of the current pathologic, molecular, and genetic features of nodal lymphomas. We want to highlight the importance of performing a consistent panel of TFH immunostains and mutational studies in TCLs to identify TFH lymphomas.

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FER and FES tyrosine kinase fusions in follicular T-cell lymphoma

Cited by 20 publications

References 24 publications

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

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

Tyrosine kinases in nodal peripheral T-cell lymphomas

Pathologic and molecular insights in nodal T-follicular helper cell lymphomas

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