Detection of Gene Fusion Transcripts in Peripheral T-Cell Lymphoma Using a Multiplexed Targeted Sequencing Assay

Drieux, Fanny; Ruminy, Philippe; Sater, Vincent; Marchand, Vinciane; Fataccioli, Virginie; Lanic, Marie-Delphine; Viennot, Mathieu; Viailly, Pierre‐Julien; Sako, Nouhoum; Robe, Cyrielle; Dupuy, Aurélie; Vallois, David; Veresezan, Liana; Poullot, Elsa; Picquenot, Jean‐Michel; Bossard, Céline; Parrens, Marie; Lemonnier, François; Jardin, Fabrice; Leval, Laurence de; Gaulard, Philippe

doi:10.1016/j.jmoldx.2021.04.013

Cited by 24 publications

(27 citation statements)

References 52 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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“…Thus, we identified two different TP63-fusion genes: FOXK2::TP63 generated by t(3;17)(q28;q25) in CTCL cell line HH, and TBL1XR1::TP63 in T-LGL cell line MOTN-1. The fusion gene FOXK2::TP63 represents a novel finding, while TPL1XR1::TP63 has been detected in both diffuse large B-cell lymphoma and peripheral T-cell lymphoma patients, generated by inv(3)(q26q28) [ 13 , 14 , 15 , 27 ].…”

Section: Resultsmentioning

confidence: 99%

“…In CTCL, various fusion genes have been described, including PCM1::JAK2, TBL1XR1::TP63, and ATXN1::TP63 [ 2 , 10 , 11 , 12 ]. Rearrangements of TP63, including TP63 fusions, are frequently described in several types of T-cell lymphoma, where they operate oncogenically via the generation of a truncated factor [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Genomic Aberrations Generate Fusion Gene FOXK2::TP63 and Activate NFKB1 in Cutaneous T-Cell Lymphoma

et al. 2022

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Cutaneous T-cell lymphoma (CTCL) is a severe lymphoid malignancy with a worse prognosis lacking curative treatment regimens. Several gene mutations and deregulated pathways, including NFkB signaling, have been implicated in its pathogenesis. Accordingly, CTCL cell line HUT-78 reportedly contains mutated NFKB2, which is constitutively activated via partial gene deletion, also demonstrating that genomic rearrangements cause driving mutations in this malignancy. Here, along with HUT-78, we analyzed CTCL cell line HH to identify additional aberrations underlying gene deregulation. Karyotyping and genomic profiling of HH showed several rearrangements worthy of detailed investigation. Corresponding to the established karyotype, RNA-seq data and PCR analysis confirmed the presence of t(3;17)(q28;q25), generating a novel fusion gene, FOXK2::TP63. Furthermore, chromosomal rearrangement t(1;4)(p32;q25) was connected to amplification at 4q24–26, affecting aberrant NFKB1 overexpression thereat. Transcription factor binding-site analysis and knockdown experiments demonstrated that IRF4 contributed to NFKB1 expression. Within the same amplicon, we identified amplification and overexpression of NFkB signaling activator CAMK2D (4q26) and p53-inhibitor UBE2D3 (4q24). Genomic profiling data for HUT-78 detailed a deletion at 10q25 underlying reported NFKB2 activation. Moreover, amplifications of ID1 (20q11) and IKZF2 (2q34) in this cell line drove overexpression of these NK cell differentiation factors and possibly thus formed corresponding lineage characteristics. Target gene analysis for NFKB1 via siRNA-mediated knockdown in HH revealed activation of TP63, MIR155, and NOTCH pathway component RBPJ. Finally, treatment of HH with NFkB inhibitor demonstrated a role for NFkB in supporting proliferation, while usage of inhibitor DAPT showed significant survival effects via the NOTCH pathway. Collectively, our data suggest that NFkB and/or NOTCH inhibitors may represent reasonable treatment options for subsets of CTCL patients.

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“…ITK-SYK transcripts were initially reported in 17% of PTCL-NOS, but not in the cases of AITL and ALK − ALCL [ 54 ]. Most of the cases with ITK-SYK were later confirmed as Tfh like-PTCL [ 55 ]. ITK-SYK proteins were demonstrated in Jurkat cells to activate the IL2RG/JAK3/STAT5 signaling pathway, which was associated with the abundant secretion of IL-2 and IL-21 [ 56 ].…”

Section: Activating Mutations In Genes Related To Tcr Signaling In Ptclsmentioning

confidence: 99%

Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma

Liu

Ning

Liu

et al. 2022

Cancers

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Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3.

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Detection of Gene Fusion Transcripts in Peripheral T-Cell Lymphoma Using a Multiplexed Targeted Sequencing Assay

Cited by 24 publications

References 52 publications

Genomic profiling for clinical decision making in lymphoid neoplasms

Genomic profiling for clinical decision making in lymphoid neoplasms

Genomic Aberrations Generate Fusion Gene FOXK2::TP63 and Activate NFKB1 in Cutaneous T-Cell Lymphoma

Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma

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