Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified.
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ABSTRACT:
SUBMITTER: Debackere K
PROVIDER: S-EPMC8211700 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:FYN-TRAF3IP2 expression in hematopoietic progenitors induces T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. To investigate the oncogenic activity of FYN-TRAF3IP2, we analyzed the lymphomagenic effects of expressing this gene fusion alone and in cooperation with loss of the Tet2 tumor suppressor gene in vivo. In these experiments, we first infected hematopoietic progenitors from CD4-specific tamoxifen-inducible Cre Tet2 conditional knockout mice (CD4 Cre-ERT2, Tet2fl/fl) with bicistronic retroviruses expressing wild type TRAF3IP2 and GFP, FYN-TRAF3IP2 and GFP, or GFP alone and injected these intravenously into isogenic recipients. Transplanted mice were then treated with vehicle only, to test the oncogenic effects of TRAF3IP2, FYN-TRAF3IP2 or GFP expression; or with tamoxifen, to evaluate the effects of TRAF3IP2, FYN-TRAF3IP2 or GFP expression in concert with genetic loss of Tet2 in CD4 T cells. In this setting, all animals transplanted with GFP-expressing progenitors remained lymphoma free at the end of follow up and one animal transplanted with wild type TRAF3IP2 GFP expressing cells developed a CD8+ T cell lymphoma. In contrast, 4/10 (40%) vehicle treated mice transplanted with FYN-TRAF3IP2-expressing cells and 5/10 (50%) tamoxifen treated mice transplanted with FYN-TRAF3IP2-expressing cells developed clonal CD4-restricted mature T cell lymphomas. To further analyze the lymphomagenic effect of the fusion gene, we performed transcriptomic profiling of FYN-TRAF3IP2-induced mouse CD4+ GFP+ PTCL tumor lymphocytes compared with normal mouse CD4+ T cells by RNAseq.
2020-10-01 | GSE138416 | GEO
Project description:T-cell lymphomas are rare malignancies that are often found in older individuals. Here we present the case of a 63 year old female that presented with diffuse cervical, inguinal, and axillary lymphadenopathy with associated weight loss and night sweats. The patient underwent excisional lymph node biopsy which revealed a T-cell lymphoma with findings characteristic of peripheral T-cell lymphoma, not otherwise specified.
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Project description:FYN-TRAF3IP2 activating fusion oncogene in peripheral T-cell lymphoma
| PRJNA575793 | ENA
Project description:Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack driver actionable targets for directed therapies in most cases. Here we identify FYN-TRAF3IP2 as a recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, we show that FYN-TRAF3IP2 leads to aberrant NF-κB signaling downstream of T cell receptor activation. Consistent with a driver oncogenic role, FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Moreover, abrogation of NF-κB signaling in FYN-TRAF3IP2-induced tumors with IκB kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results demonstrate an oncogenic and pharmacologically targetable role for FYN-TRAF3IP2 in PTCLs and call for the clinical testing of anti-NF-κB targeted therapies in these diseases.
| S-EPMC8081346 | biostudies-literature
Project description:Due to heterogeneous morphological and immunophenotypic features, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified. These conditions have an aggressive course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particularly methylation and acetylation, are generally involved in chromatin state regulation. Here we screened the core set of genes related to histone methylation (KMT2D, SETD2, KMT2A, KDM6A) and acetylation (EP300, CREBBP) and identified 59 somatic mutations in 45 of 125 (36.0%) patients with peripheral T-cell lymphomas, not otherwise specified. Histone modifier gene mutations were associated with inferior progression-free survival time of the patients, irrespective of chemotherapy regimens, but an increased response to the histone deacetylase inhibitor chidamide. In vitro, chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine. Mechanistically, decitabine acted synergistically with chidamide to enhance the interaction of KMT2D with transcription factor PU.1, regulated H3K4me-associated signaling pathways, and sensitized T-lymphoma cells to chidamide. In a xenograft KMT2D-mutated T-lymphoma model, dual treatment with chidamide and decitabine significantly retarded tumor growth and induced cell apoptosis through modulation of the KMT2D/H3K4me axis. Our work thus contributes to the understanding of aberrant histone modification in peripheral T-cell lymphomas, not otherwise specified and the stratification of a biological subset that can benefit from epigenetic treatment.
| S-EPMC5865443 | biostudies-literature
Project description:PurposeThe significance of Epstein-Barr virus (EBV) infections for the prognosis of patients with peripheral T-cell lymphomas (PTCLs), specifically angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS), remains unclear. The Epstein-Barr encoding region can be used to detect EBV in tissue sections by in situ hybridization (ISH) and by polymerase chain reaction (PCR) assays of peripheral blood samples from patients with PTCLs. This study compared the outcomes patients with AITL or PTCL-NOS for whom the presence of EBV infection was assessed by these two methods.Patients and methodsThis was a retrospective study of patients newly diagnosed with AITL or PTCL-NOS. All patients were selected from a single transplantation center. EBV-positive lymphomas were detected at the time of diagnosis in tissue sections by ISH or in the blood by PCR.ResultsOut of a cohort of 140 patients with histologically confirmed AITL or PTCL-NOS, 105 were EBV-positive. The 3-year overall survival of patients with EBV-positive TCL was 43.3% compared to 68.6% in patients with EBV-negative TCL (p = .01). Patients who were treated with autologous or allogeneic hematopoietic stem cell transplantation (n = 28 and n = 11, respectively) or chemotherapy alone (n = 66) had 3-year survival rates of 67.0%, 62.3%, and 30.2%, respectively (p <.02). Patients with EBV-positive TCL had a better prognosis after treatment with hematopoietic stem cell transplantation compared to chemotherapy alone, but no difference was seen among patients with EBV-negative TCL.ConclusionsEBV infection was shown to negatively affect the clinical outcomes of patients with TCL. Stem cell transplantation has been found to be an effective treatment for EBV-associated lymphomas. Further investigations are warranted to determine the optimal treatment for these patients.
| S-EPMC8786732 | biostudies-literature
Project description:Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with genomic aberrations has been shown to resemble lymphoma-type adult T-cell leukemia/lymphoma (ATLL) in terms of its genomic aberration patterns, histopathology, and prognosis. We have shown recently that a majority of patients with acute-type ATLL have multiple subclones that were likely produced in lymph nodes. In this study, we analyzed whether PTCL, NOS with genomic aberrations also has multiple subclones as found in ATLL by means of high-resolution oligo-array comparative genomic hybridization (CGH). Thirteen cases of PTCL, NOS were available for 44K high-resolution array CGH analysis. The results showed that 11 (84.6%) of the 13 cases had a log2 ratio imbalance, suggesting that multiple subclones exist in PTCL, NOS with genomic aberrations. In order to analyze the association between multiple subclones and prognosis, we used previous bacterial-artificial chromosome (BAC) array analyses for 29 cases and found that the existence of multiple subclones was associated with a poor prognosis (P = 0.0279).
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Project description:Peripheral T-cell lymphomas not otherwise specified (PTCLs/NOS) are rare and aggressive tumours whose molecular pathogenesis and diagnosis are still challenging. The microRNA (miRNA) profile of 23 PTCLs/NOS was generated and compared with that of normal T-lymphocytes (CD4+, CD8+, naive, activated). The differentially expressed miRNA signature was compared with the gene expression profile (GEP) of the same neoplasms. The obtained gene patterns were tested in an independent cohort of PTCLs/NOS. The miRNA profile of PTCLs/NOS then was compared with that of 10 angioimmunoblastic T-cell lymphomas (AITLs), 6 anaplastic large-cell lymphomas (ALCLs)/ALK+ and 6 ALCLs/ALK-. Differentially expressed miRNAs were validated in an independent set of 20 PTCLs/NOS, 20 AITLs, 19 ALCLs/ALK- and 15 ALCLs/ALK+. Two hundred and thirty-six miRNAs were found to differentiate PTCLs/NOS from activated T-lymphocytes. To assess which miRNAs impacted on GEP, a multistep analysis was performed, which identified all miRNAs inversely correlated to different potential target genes. One of the most discriminant miRNAs was selected and its expression was found to affect the global GEP of the tumours. Moreover, two sets of miRNAs were identified distinguishing PTCL/NOS from AITL and ALCL/ALK-, respectively. The diagnostic accuracy of this tool was very high (83.54%) and its prognostic value validated.
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Project description:In this retrospective study, we report 70 cases of Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) among 1696 DLBCL-NOS cases diagnosed between 2006 and 2019 (prevalence of 4.1%). At diagnosis, median age was 68.5 years; 79% of the cases presented with an advanced-stage disease (III-IV), 48% with extranodal lesions, and 14% with an hemophagocytic lymphohistiocytosis (HLH) (8 at diagnosis and 1 on therapy). A total of 46 cases presented a polymorphic pattern, and 21 were monomorphic. All had a non-germinal center B phenotype, with the majority of tumor cells expressing CD30 and programmed death ligand 1 (98% and 95%, respectively). Type II and III EBV latency was seen in 88% and 12% of the cases, respectively. Patients were treated with immunochemotherapy (59%) or chemotherapy (22%), and 19% received palliative care due to advanced age and altered performance status. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival (OS) at 5 years were 52.7% and 54.8%, respectively. Older age (>50 years) and HLH were associated with shorter PFS and OS in multivariate analysis (PFS: hazard ratio [HR], 14.01; 95% confidence interval [CI], 2.34-83.97; and HR, 5.78; 95% CI, 2.35-14.23; OS: HR, 12.41; 95% CI, 1.65-93.53; and HR, 6.09; 95% CI, 2.42-15.30, respectively). Finally, using a control cohort of 425 EBV- DLBCL-NOS, EBV positivity was associated with a shorter OS outcome within patients >50 years (5-year OS, 53% [95% CI, 38.2-74] vs 60.8% [95% CI, 55.4-69.3], P = .038), but not in younger patients.
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Project description:Survival outcome of patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL-NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure-free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow-up duration of 52 months, 240 patients (135 PTCL-NOS, 105 AITL) experienced progression/relapse. In patients with PTCL-NOS, the median durations of FFS1, FFS2 and FFS3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL, they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999-2004, 2005-2009 and 2010-2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5-year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5-year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.
| S-EPMC5836501 | biostudies-literature