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Peripheral T-cell lymphomas comprise 8% of the malignant lymphomas in Germany. About 25% of these cases present primarily in extranodal localizations. Such localizations are typical for the respective disease and form the basis for the classification of extranodal peripheral T-cell lymphoma. The morphology, immunophenotype and lineage specificity of the tumor cells (originating from T- or NK-cells) is only secondary for the classification. Extranodal NK/T-cell lymphomas of the nasal type are characterized by an angiocentric growth pattern and large confluent areas of necrosis. In addition, there is a clonal infection by Epstein-Barr virus in the T-lymphocytes. In the differential diagnosis, B-cell lymphomas are more frequent at all localizations than T- or NK-cell lymphomas.
Peripheral T cell lymphomas (PTCLs) are a heterogeneous entity of neoplasms with poor prognosis, lack of effective therapies, and a largely unknown pathophysiology. Identifying the mechanism of lymphomagenesis and cell-of-origin from which PTCLs arise is crucial for the development of efficient treatment strategies. In addition to the well-described thymic lymphomas, we found that p53-deficient mice also developed mature PTCLs that did not originate from conventional T cells but from CD1d-restricted NKT cells. PTCLs showed phenotypic features of activated NKT cells, such as PD-1 up-regulation and loss of NK1.1 expression. Injections of heat-killed Streptococcus pneumonia, known to express glycolipid antigens activating NKT cells, increased the incidence of these PTCLs, whereas Escherichia coli injection did not. Gene expression profile analyses indicated a significant down-regulation of genes in the TCR signaling pathway in PTCL, a common feature of chronically activated T cells. Targeting TCR signaling pathway in lymphoma cells, either with cyclosporine A or anti-CD1d blocking antibody, prolonged mice survival. Importantly, we identified human CD1d-restricted lymphoma cells within Vδ1 TCR-expressing PTCL. These results define a new subtype of PTCL and pave the way for the development of blocking anti-CD1d antibody for therapeutic purposes in humans.
Peripheral T-cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are common in Japan. ATLL is an incurable T-cell malignancy induced by human T-cell lymphotropic virus type 1 (HTLV-1). The global genomics of ATLL can be summarized as alterations involving T-cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral-mediated T-cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV-1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL-related genes is identified in a part of HTLV-1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL-NOS is a heterogeneous disease type of T-cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL-NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.
Telomere length is maintained by the activation of telomerase, which causes continuous cell division and proliferation in many carcinomas. A catalytic reverse transcriptase protein (TERT) encoded by the TERT gene plays a critical role in the activation of telomerase. We performed a molecular and pathological analysis of the TERT against three different peripheral T-cell lymphoma (PTCL) subtypes: PTCL, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and adult T-cell leukemia/lymphoma (ATLL). Immunohistochemical analysis demonstrated TERT expression in 31% of AITL, 11% of PTCL-NOS, and 5% of ATLL. Among them, AITL frequently showed high TERT expression with statistical significance. TERT promoter mutation analysis and genomic copy number evaluation were performed. TERT promoter mutation was observed in two cases of PTCL-NOS (2/40) and not in other PTCLs. Genome copy number amplification was detected in 33% of PTCL-NOS, 33% of AITL, and 50% of ATLL cases. We evaluated the relationship between the analyzed TERT genomic abnormalities and protein expression; however, no apparent relationship was observed. Furthermore, immunostaining showed TERT expression in the PTCL cytoplasm, suggesting the existence of mechanisms other than the maintenance of telomere length. Statistical analysis of the effect of TERT expression on the prognosis in PTCL cases revealed that TERT expression tended to have a poor prognosis in PTCL-NOS. Since TERT expression was not an independent factor in multivariate analysis, further research will be needed to clarify the poor prognosis of PTCL-NOS in TERT expression.
Natural killer (NK) cells are well known to be the most important effector cells mediating antibody-dependent cellular cytotoxicity (ADCC) which is an important mechanism of action of antibody drugs. We evaluated the effects of chemotherapy on the cell number and activity of NK cells from patients who received the vincristine-cyclophosphamide-doxorubicin-prednisone (VCAP), doxorubicin-ranimustine-prednisone (AMP), and vindesine-etoposide-carboplatin-prednisone (VECP) (mLSG15) or mLSG15-like (-L) regimen, which is one of the standard of cares for newly diagnosed adult T-cell leukemia-lymphoma (ATL), or the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) or CHOP-L regimen which is another standard of care for ATL and peripheral T-cell lymphoma (PTCL).
Recurrent gain-of-function mutations in the transcription factors STAT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8+ T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8+ T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia in vivo We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.
Peripheral T-cell lymphomas (PTCL) are generally less common and pursue a more aggressive clinical course than B-cell lymphomas, with the T-cell phenotype itself being a poor prognostic factor in adult non-Hodgkin lymphoma (NHL). With notable exceptions such as ALK(+) anaplastic large cell lymphoma (ALCL, ALK+), the molecular abnormalities in PTCL remain poorly characterised. We had previously identified circulating antibodies to ALK in patients with ALCL, ALK(+). Thus, as a strategy to identify potential antigens associated with the pathogenesis of PTCL, not otherwise specified (PTCL, NOS), we screened a testis cDNA library with sera from four PTCL, NOS patients using the SEREX (serological analysis of recombinant cDNA expression libraries) technique. We identified nine PTCL, NOS-associated antigens whose immunological reactivity was further investigated using sera from 52 B- and T-cell lymphoma patients and 17 normal controls. The centrosomal protein CEP250 was specifically recognised by patients sera and showed increased protein expression in cell lines derived from T-cell versus B-cell malignancies. TCEB3, BECN1, and two previously uncharacterised proteins, c14orf93 and ZBTB44, were preferentially recognised by patients' sera. Transcripts for all nine genes were identified in 39 cancer cell lines and the five genes encoding preferentially lymphoma-recognised antigens were widely expressed in normal tissues and mononuclear cell subsets. In summary, this study identifies novel molecules that are immunologically recognised in vivo by patients with PTCL, NOS. Future studies are needed to determine whether these tumor antigens play a role in the pathogenesis of PTCL.
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.
Peripheral T-cell lymphoma (PTCL) is a rare, aggressive, heterogeneous, Non-Hodgkin's lymphoma with poor prognosis and inadequate response to current therapies. Recent sequencing studies indicate a prevalence of activating mutations in the JAK/STAT signaling pathway. Oncogenic mutations in STAT5B, observed in approximately one third of cases of multiple different PTCL subtypes, correlate with inferior patient outcomes. Therefore, interest in the development of therapeutic strategies for targeting STAT5 in PTCL is warranted. In this study, we show that the drug pimozide inhibits STAT5 in PTCL, leading to apoptotic cell death by means of the TRAIL/DR4 dependent extrinsic apoptotic pathway. Pimozide induced PTCL cell death is caspase 8 dependent, increases the expression of the TRAIL receptor, DR4, on the surface of pre-apoptotic PTCL cells, and enhances TRAIL induced apoptosis in a TRAIL dependent manner. In parallel, we show that mRNA and protein levels of intrinsic pathway BCL-2 family members and mitochondrial membrane potential remain unaffected by STAT5 knockdown and/or inhibition. In primary PTCL patient samples, pimozide inhibits STAT5 activation and induces apoptosis. Our data support a role for STAT5 inhibition in PTCL and implicate potential utility for inhibition of STAT5 and activation of the extrinsic apoptotic pathway as combination therapy in PTCL.
DNA methyltransferase 3A (DNMT3A) is an enzyme involved in DNA methylation that is frequently mutated in human hematologic malignancies. We have previously shown that inactivation of Dnmt3a in hematopoietic cells results in chronic lymphocytic leukemia in mice. Here we show that 12% of Dnmt3a-deficient mice develop CD8+ mature peripheral T cell lymphomas (PTCL) and 29% of mice are affected by both diseases. 10% of Dnmt3a+/- mice develop lymphomas, suggesting that Dnmt3a is a haploinsufficient tumor suppressor in PTCL. DNA methylation was deregulated genome-wide with 10-fold more hypo- than hypermethylated promoters and enhancers, demonstrating that hypomethylation is a major event in the development of PTCL. Hypomethylated promoters were enriched for binding sites of transcription factors AML1, NF-κB and OCT1, implying the transcription factors potential involvement in Dnmt3a-associated methylation. Whereas 71 hypomethylated genes showed an increased expression in PTCL, only 3 hypermethylated genes were silenced, suggesting that cancer-specific hypomethylation has broader effects on the transcriptome of cancer cells than hypermethylation. Interestingly, transcriptomes of Dnmt3a+/- and Dnmt3aΔ/Δ lymphomas were largely conserved and significantly overlapped with those of human tumors. Importantly, we observed downregulation of tumor suppressor p53 in Dnmt3a+/- and Dnmt3aΔ/Δ lymphomas as well as in pre-tumor thymocytes from 9 months old but not 6 weeks old Dnmt3a+/- tumor-free mice, suggesting that p53 downregulation is chronologically an intermediate event in tumorigenesis. Decrease in p53 is likely an important event in tumorigenesis because its overexpression inhibited proliferation in mouse PTCL cell lines, suggesting that low levels of p53 are important for tumor maintenance. Altogether, our data link the haploinsufficient tumor suppressor function of Dnmt3a in the prevention of mouse mature CD8+ PTCL indirectly to a bona fide tumor suppressor of T cell malignancies p53.
T-cell clonality of peripheral T-cell lymphoma (PTCL) is routinely evaluated with a PCR-based method using genomic DNA. However, there are limitations with this approach. The purpose of this study was to determine the utility of RNA-seq for assessing T-cell clonality and T-cell antigen receptor (TCR) repertoire of the neoplastic T-cells in 108 PTCL samples. TCR transcripts, including complementarity-determining region 3 (CDR3) sequences, were assessed. In normal T cells, the CDR3 sequences were extremely diverse, without any clonotype representing more than 2% of the overall TCR population. Dominant clones could be identified in 65 out of 76 PTCL cases (86%) with adequate TCR transcript expression. In monoclonal cases, the dominant clone varied between 11% and 99% of TCRβ transcripts. No unique Vα or Vβ usage was observed. Small T-cell clones were often observed in T- and NK-cell tumors in a percentage higher than observed in reactive conditions. γ chain expression was very low in tumors expressing TCRαβ, but its expression level was high and clonality was detected in a TCRγδ expressing tumor. NK cell lymphoma (NKCL) did not express significant levels of TCR Vβ or Vγ genes. RNA-seq is a useful tool for detecting and characterizing clonal TCR rearrangements in PTCL.
Peripheral T cell lymphoma (PTCL) has a poor prognosis. Overexpression of vascular endothelial growth factor (VEGF) might contribute to the poor prognosis of PTCL and could be the target of novel therapy. The efficacy and safety of recombinant human endostatin (Endostar) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (ECHOP) have been explored in 15 PTCL patients. The objective response rate was 80%, with 53.3% patients having achieved complete response (CR) rate. The CR rate was 100% (3/3) in angioimmunoblastic T cell lymphoma (AITL) patients compared to only 36.4% (4/11) in PTCL not otherwise specified (PTCL-NOS) patients. With a median follow-up of 69 months, the 5-year progression-free survival and overall survival (OS) were 53% and 60%, respectively. The 5-year OS was 100% in AITL but was only 45% in PTCL-NOS. Seven out of 11 patients showed overexpression of VEGFR2 in their tumor vessels and had a better efficacy than those with low expression of VEGFR2. Grade 3 or 4 neutropenia is the most common toxicity observed. ECHOP was safe and might display potential benefit in AITL patients.
Peripheral T cell lymphomas (PTCLs) are associated with a poor prognosis due to often advanced disease at the time of diagnosis and due to a lack of efficient therapeutic options. Therefore, appropriate animal models of PTCL are vital to improve clinical management of this disease. Here, we describe a monoclonal CD8(+) CD4(-) αβ T cell receptor Vβ2(+) CD28(+) T cell lymphoma line, termed T8-28. T8-28 cells were isolated from an un-manipulated adult BALB/c mouse housed under standard pathogen-free conditions. T8-28 cells induced terminal malignancy upon adoptive transfer into syngeneic BALB/c mice. Despite intracellular expression of the cytotoxic T cell differentiation marker granzyme B, T8-28 cells appeared to be defective with respect to cytotoxic activity as read-out in vitro. Among the protocols tested, only addition of interleukin 2 in vitro could partially compensate for the in vivo micro-milieu in promoting growth of the T8-28 lymphoma cells.
Peripheral T cell lymphomas (PTCLs) have an overall poor prognosis. Indeed, registry data in elderly patients show that the median progression-free survival (mPFS) following first- and second-line therapies are only 6.7 and 3.1 months, respectively. The aim of the study is to show the activity of metronomic chemotherapy, a regular administration of low chemotherapeutic drug doses allowing a favourable toxicity profile, on elderly PTCL patients.
We performed a retrospective analysis to identify risk factors and survival outcome for central nervous system (CNS) relapse of peripheral T-cell lymphoma (PTCL) by histologic type. Records of 600 PTCL patients diagnosed between 1999 and 2014 were analyzed including PTCL not otherwise specified (PTCL-NOS, 174 patients), angoimmunoblastic T-cell lymphoma (AITL, 144), ALK+anaplastic large cell lymphoma (ALCL, 74), ALK-ALCL (103), extranodal NK-cell lymphoma (ENKL, 54), or others (51). With a median follow up of 57 months, 13 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 ENKL) experienced CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.5% (95%CI: 0.7-2.8%) and 2.1% (95%CI: 1.1-3.5%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.4% in ALK+ALCL, 2.1% in ALK-ALCL and 3.7% in ENKL. Extranodal involvement >1 site was the only significant factor associated with higher chance of CNS relapse (HR: 4.9, 95%CI: 1.6-15.0, p = 0.005). Patients with ALK+ALCL who had extranodal involvement >1 (N = 19) had very high risk of CNS relapse with one year cumulative incidence of 17% (95%CI: 4%-37%), all occurring within six months after diagnosis. All patients with CNS relapse eventually died (median, 1.5 months; range, 0.1-10.1 months). CNS relapse in patients with PTCL is rare event but the risk varies by subtype. ALK+ALCL patients with extranodal involvement >1 site have a very high risk of early CNS relapse, and thus evaluation of CNS involvement at the time of diagnosis and possible CNS-directed prophylaxis may be considered.
Chidamide (CS055) is a new and highly selective histone deacetylase inhibitor displaying significant single-agent activity in peripheral T-cell lymphoma (PTCL). But there is little known the synergistic effect between CS055 and chemotherapy. The purpose of this study is to explore the synergistic effect and molecular mechanisms of CS055 combination with Doxorubicin in PTCL cells. We found that CS055 showed dose- and time-dependent inhibition effects on PTCL cell. Meanwhile, the synergistic effect was significantly observed after combination treatment with lower drug-concentration of CS055 and Doxorubicin. Lower drug-concentration of CS055 induced weak apoptosis in PTCL cells, but combination treatment with CS055 and Doxorubicin promoted more significant apoptosis. Combination treatment with CS055 and Doxorubicin significantly changed mitochondrial membrane potential and H3 acetylated level, resulting in up-regulating DNA damage protein p-γH2AX and apoptosis proteins including cleaved-caspase-3, cleaved-caspase-9 and cleaved-PARP, and down-regulating anti-apoptosis protein Bcl-2. In a word, Doxorubicin could increase the CS055-induced inhibition effects on PTCL cells, suggesting that CS055 combination with Doxorubicin or Doxorubicin-based chemotherapy drugs might be a new therapy approach for PTCL patients.
Objective To determine the efficacy and prognosis of autologous hematopoietic stem cell transplantation (ASCT) as frontline treatment for peripheral T cell lymphoma (PTCL). Methods Clinical data from 46 PTCL patients who achieved complete (CR) or partial remission (PR) after ASCT from October 1996 to July 2014 were analysed retrospectively. Results Median patient age was 32 (range: 15-68) years. Disease types included PTCL, unspecified type, in 23 patients, anaplastic large cell lymphoma in eight, angioimmunoblastic lymphoma in eight, extranodal NK/T-cell lymphoma in five, and hepatosplenic T-cell lymphoma and enteropathy associated T-cell lymphoma in one each. Of these patients, 80% had Prognostic Index for Peripheral T-cell Lymphoma scores ≥1. Thirty-four patients had pre-transplantation CR and 12 had PR. Median follow up was 37 (6-176) months. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 77.1% and 61.9%, respectively. Multivariate analysis showed that pre-transplantation CR was an independent risk factor for survival, and CR was more common than PR (OS 81% vs 59.3%; PFS 71.8% vs 17.8%). Conclusion Frontline consolidation treatment with ASCT was associated with favourable outcomes in patients with PTCL. Pre-transplantation CR was a prognostic factor for survival, suggesting that ASCT may be favoured as front-line consolidation therapy after first complete remission.
Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
This study evaluated the prognostic significance of FDG PET/CT in patients with nodal peripheral T-cell lymphoma (PTCL). We retrospectively reviewed patients with histologically confirmed nodal PTCL who underwent FDG PET/CT at baseline, after three cycles of first-line chemotherapy (interim), and at the end of therapy. Response was assessed visually using the Deauville 5-point scale (D5PS); scores of 1, 2, and 3 were considered PET-negative, and scores of 4 and 5 were considered PET-positive. The associations between FDG PET/CT findings and survival were assessed using Cox regression analysis. A total of 79 patients (44 males and 35 females; median age 56 years) were included in this study. In response assessment, 17 (22%) had an interim PET-positive result and 10 (13%) had an end-of-therapy PET-positive result. During a median follow-up of 50 months, 37 patients (47%) presented with disease progression and 30 patients (38%) died. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 57% and 64%, respectively. An interim PET-positive result was the only significant indicator of PFS. Higher International Prognostic Index and end-of-therapy PET-positive result were significant independent prognostic factors of OS. Interim and end-of-therapy FDG PET/CT responses based on D5PS are meaningful in predicting the outcomes of patients with nodal PTCL.
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