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

Debackere, Koen; Marcelis, Lukas; Demeyer, Sofie; Bempt, Marlies Vanden; Mentens, Nele; Gielen, Olga; Jacobs, Kris; Broux, Michaël; Verhoef, Gregor; Michaux, Lucienne; Graux, Carlos; Włodarska, Iwona; Gaulard, Philippe; Leval, Laurence de; Tousseyn, Thomas; Cools, Jan; Dierickx, Daan

doi:10.1038/s41467-021-24037-4

Cited by 23 publications

(23 citation statements)

References 60 publications

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“…In follicular helper T-cell lymphoma (TFHL) and peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS), most common genetic abnormalities, including SNVs, CNAs, and rearrangements, affect genes of epigenetic regulators (eg, TET2, DNMT3A, IDH2), T-cell receptor (TcR) signaling and activation (eg, RHOA, VAV1, CD28, ICOS, FYN, LCK), phosphatidylinositol 3-kinase/protein kinase B pathway, and tumor suppressor genes (eg, TP53, CDKN2A, ATM, PTEN, RB1). [279][280][281][282][283][284] (supplemental Figure 1) Genetic testing of newly diagnosed nodal PTCL for commonly reported alterations, ideally using HTSbased panels targeting tumor DNA with high depth and, if necessary, RNA, may be clinically useful as the genomic profile may have implications for accurate diagnosis, risk stratification, and therapy selection (Table 2; Figure 5).…”

Section: Tfh Lymphoma and Peripheral T-cell Lymphoma Nosmentioning

confidence: 99%

Genomic profiling for clinical decision making in lymphoid neoplasms

Leval

Alizadeh

Bergsagel

et al. 2022

Blood

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With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. While the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses and epigenetic profiling will be discussed, as these will likely become important future tools for implementing precision medicine approaches in clinical decision-making for patients with lymphoid malignancies.

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Section: Tfh Lymphoma and Peripheral T-cell Lymphoma Nosmentioning

confidence: 99%

Genomic profiling for clinical decision making in lymphoid neoplasms

Leval

Alizadeh

Bergsagel

et al. 2022

Blood

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“…To gain a deeper understanding of the mechanisms that drive PTCL development, we carried out RNA-sequencing (RNA-seq) on 28 PTCL samples, including 23 PTCL, not otherwise specified (PTCL-NOS) cases, 2 ALCL cases and 3 Follicular T cell lymphoma (FTCL) cases 4 . In 5 of these 28 PTCL cases (18%), we identified aberrant overexpression of MYCN (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Efforts to fully characterize the genetic and transcriptomic landscape of the different PTCL entities are currently ongoing. In line with this, we have previously performed whole transcriptome sequencing of a cohort of 28 clinical PTCL cases to identify novel oncogenic fusion genes 4 .…”

Section: Introductionmentioning

confidence: 95%

Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T cell lymphoma

Bempt

Debackere

Demeyer

et al. 2022

Preprint

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Peripheral T cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T cell lymphoma that recapitulated human PTCL with a MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential co-factor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity, but dependent on phosphorylation by CDK1. MYCN-driven T cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with FDA-approved HDAC inhibitors.

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“…The dataset used was the Vav1 ΔC ‐associated gene signature generated in the adoptive transfer experiments with VAV1 ΔC ‐expressing CD4 + T cells [ 29 ]. To evaluate the gene signature fitness across the mouse Rhoa G17V and Tet2 mutant CD4 + T cell signatures [ 37 ], the mouse GAPDH‐overexpressing T cell signature [ 38 ], the mouse FYN‐TRAF3IP2‐overexpressing bone marrow progenitors signature [ 39 ] and the mouse T FH and T H1 cell signatures in the presence or absence of Tbx21 [ 40 ], the enrichment scores for both the upregulated and downregulated signatures found in Trp53 ER/ER ; Vav1 ΔC/ΔC ‐transformed AITL cells were calculated using single‐sample GSEA. The difference between the two normalized enrichment scores (NES) yielded the fit score, a measure of the enrichment and depletion of the upregulated and downregulated signatures, respectively.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the spectrum of trivalent VAV1‐mutation‐driven tumours using a gene‐edited mouse model

et al. 2022

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Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall‐cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene‐edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild‐type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell‐type‐specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.

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

Cited by 23 publications

References 60 publications

Genomic profiling for clinical decision making in lymphoid neoplasms

Genomic profiling for clinical decision making in lymphoid neoplasms

Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T cell lymphoma

Characterization of the spectrum of trivalent VAV1‐mutation‐driven tumours using a gene‐edited mouse model

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