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1.
Dtsch Med Wochenschr ; 144(20): 1400-1404, 2019 10.
Artigo em Alemão | MEDLINE | ID: mdl-31594013

RESUMO

NEW WHO CLASSIFICATION 2016 FOR LYMPHOMA AND MOLECULAR MARKER: The new WHO 2016 Classification for Lymphomas included more detailed definitions of individual entities, such as: the Anaplastic Large Cell Lymphoma, ALK; the terminus of enteropathy-associated T-cell lymphoma (EATCL, type 1) now is restricted to celiac-associated form. The integration of next Generation sequencing (NGS) enables better differential diagnostics, e. g. angioimmunoblastic lymphoma (AITL) can be characterized by the presence of TET2, RHOA, IDH2 or DNMT3A mutations. Furthermore, certain mutations also have prognostic impact. In ALCL/ALK-, evidence of a DUSP22 / IRF4 re-arrangement is associated with a better and detection of TP63 is associated with a worse prognosis. CLINICAL COURSE AND PROGNOSIS: In addition to B symptoms and nodal manifestation, extranodal manifestations such as skin infiltrates can be observed in up to 20 %. In AITL, polyclonal hypergammaglobulinemia, Coombs-positive hemolytic anemia and immunodeficiency can occur, as a sign of a dysregulated immune system. ADVANCES IN THERAPY: By combining the immunoconjugate brentuximab-vedotin with chemotherapy, improvement in disease-free and overall survival in CD30+-PTCL (especially in ALCL) was observed. FUTURE PERSPECTIVE: At present demethylating agent 5-azacytidine is explored in AITL and PTCL with a T-follicle helper type (TFH).


Assuntos
Linfoma de Células T Periférico , Antineoplásicos/uso terapêutico , Análise Mutacional de DNA , Diagnóstico Diferencial , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoconjugados/uso terapêutico , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/terapia , Mutação/genética
2.
Cancer Biomark ; 25(3): 259-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282408

RESUMO

BACKGROUND: The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated. METHODS: The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia. RESULTS: In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL). CONCLUSIONS: NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.


Assuntos
Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/genética , Linfoma/genética , Neuropilina-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Imuno-Histoquímica , Linfoma/classificação , Linfoma/patologia , Linfoma/virologia , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
3.
Rinsho Ketsueki ; 60(4): 271-280, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31068555

RESUMO

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoid malignancies. Several recent comprehensive genomic studies characterize the genomic alterations of each PTCL type and reveal the complexity and heterogeneity. The updated World Health Organization classification has precisely distinguished "lymphoma" from "lymphoproliferative disorder" and has included a new entity based on the tumor phenotypes. Although establishing the classifications based on genomic alterations has been difficult because of heterogeneity, the genomic alterations may support the diagnosis. Establishing genomic alterations that act as predictive markers for clinical courses and/or therapeutic targets is needed in future studies using genomic alteration information. Since patients with PTCL generally have poor prognosis, establishing the target and standard therapies is one of the major issues to be addressed. In addition to clinicopathological and genomic analyses, patient-derived xenograft models can provide these therapeutic strategies. Integration of analyzed data is considered to promote future PTCL studies, leading to improved PTCL prognosis.


Assuntos
Linfoma de Células T Periférico/genética , Genômica , Humanos , Linfoma de Células T Periférico/classificação , Prognóstico
4.
PLoS One ; 14(4): e0215765, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31013298

RESUMO

Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquinsan/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal.


Assuntos
Antineoplásicos/administração & dosagem , Linfoma de Células T Periférico/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Heterozigoto , Humanos , Linfonodos/citologia , Linfonodos/diagnóstico por imagem , Linfonodos/efeitos dos fármacos , Linfoma de Células T Periférico/diagnóstico por imagem , Linfoma de Células T Periférico/genética , Imagem por Ressonância Magnética , Camundongos , Cultura Primária de Células , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/patologia , Resultado do Tratamento , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/genética
5.
Am J Hematol ; 94(6): 628-634, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30829413

RESUMO

The histological diagnosis of peripheral T-cell lymphoma (PTCL) can represent a challenge, particularly in the case of closely related entities such as angioimmunoblastic T-lymphoma (AITL), PTCL-not otherwise specified (PTCL-NOS), and ALK-negative anaplastic large-cell lymphoma (ALCL). Although gene expression profiling and next generations sequencing have been proven to define specific features recurrently associated with distinct entities, genomic-based stratifications have not yet led to definitive diagnostic criteria and/or entered into the routine clinical practice. Herein, to improve the current molecular classification between AITL and PTCL-NOS, we analyzed the transcriptional profiles from 503 PTCLs stratified according to their molecular configuration and integrated them with genomic data of recurrently mutated genes (RHOA G17V , TET2, IDH2 R172 , and DNMT3A) in 53 cases (39 AITLs and 14 PTCL-NOSs) included in the series. Our analysis unraveled that the mutational status of RHOA G17V , TET2, and DNMT3A poorly correlated, individually, with peculiar transcriptional fingerprints. Conversely, in IDH2 R172 samples a strong transcriptional signature was identified that could act as a surrogate for mutational status. The integrated analysis of clinical, mutational, and molecular data led to a simplified 19-gene signature that retains high accuracy in differentiating the main nodal PTCL entities. The expression levels of those genes were confirmed in an independent cohort profiled by RNA-sequencing.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Células T Periférico , Mutação , Proteínas de Neoplasias , Transcrição Genética , Feminino , Humanos , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética
6.
Blood ; 133(15): 1664-1676, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30782609

RESUMO

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.


Assuntos
Variações do Número de Cópias de DNA , Linfoma de Células T Periférico/genética , Oncogenes , Feminino , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T Periférico/classificação , Masculino , Mutação , Proteínas com Domínio T/genética
7.
Leukemia ; 33(7): 1687-1699, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30683910

RESUMO

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/complicações , Variação Genética , Linfoma Extranodal de Células T-NK/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma de Células T Periférico/genética , Proteína 2 Ligante de Morte Celular Programada 1/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/isolamento & purificação , Humanos , Ligantes , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/virologia
8.
Cancer Treat Res ; 176: 31-68, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30596212

RESUMO

Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.


Assuntos
Perfilação da Expressão Gênica , Genômica , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/genética
9.
Am J Dermatopathol ; 41(2): 148-154, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30085957

RESUMO

Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) is a diagnosis of exclusion, showing extreme cytological and phenotypic heterogeneity. Skin involvement of PTCL may be primary or secondary. Diagnosis of histiocytosis may be difficult, requiring clinical-pathological correlation. We describe a laryngeal atypical histiocytic lesion (AHL) and a nasal PTCL, NOS with cutaneous involvement in the same patient presenting with peculiar histopathologic and immunophenotypic features. The laryngeal neoplasm showed morphological and immunophenotypic evidence of histiocytic differentiation and does not fit any other category of the WHO classification nor the revised classification of histiocytosis. The nasal and cutaneous lesions presented features close to natural killer/T-cell lymphoma and gamma-delta T-cell lymphoma but did not meet accurately the WHO criteria. A somatic activating Q61K mutation was found on exon 3 of the NRAS gene in both AHL and PTCL, NOS. The mutation on NRAS gene in both AHL and PTCL, NOS may suggest a common origin from a precursor cell.


Assuntos
Histiocitose/patologia , Doenças da Laringe/patologia , Linfoma de Células T Periférico/patologia , Neoplasias Nasais/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Feminino , GTP Fosfo-Hidrolases/genética , Histiocitose/genética , Humanos , Doenças da Laringe/genética , Linfoma de Células T Periférico/genética , Proteínas de Membrana/genética , Mutação , Neoplasias Nasais/genética , Neoplasias Cutâneas/genética
10.
Mod Pathol ; 32(2): 216-230, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30206415

RESUMO

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.


Assuntos
Implantes de Mama/efeitos adversos , Linfoma Anaplásico de Células Grandes/genética , Adulto , Feminino , Humanos , Linfoma de Células T Periférico/genética , Transcriptoma
11.
Fam Cancer ; 18(1): 113-119, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30097855

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis: the 5-year survival rate is approximately 30%. Somatic driver mutations have been found in TET2, IDH2, DNMT3A, RHOA, FYN, PLCG1, and CD28, whereas germline susceptibility to AITL has to our knowledge not been studied. The homogenous Finnish population is well suited for studies on genetic predisposition. Here, we performed an exome-wide rare variant analysis in 23 AITL patients. No germline mutations were found in the driver genes, implying that they are not frequently involved in genetic AITL predisposition. Potentially pathogenic variants present in at least two patients and showing significant (p < 0.01) enrichment in our sample set were found in ten genes: POLK, PRKCB, ZNF676, PRRC2B, PCDHGB6, GNL3L, TTC36, OTOG, OSGEPL1, and RASSF9. The most significantly enriched variants, causing p.Lys469Ter in a splice variant of POLK and p.Pro588His in PRKCB, are intriguing candidates as Polk deficient mice display a spontaneous mutator phenotype, whereas PRKCB was recently shown to be somatically mutated in 33% of another peripheral T-cell lymphoma, adult T-cell lymphoma. If validated, our findings would provide new insight into the pathogenesis of AITL, as well as tools for early detection in susceptible individuals.


Assuntos
Análise Mutacional de DNA , Predisposição Genética para Doença , Linfoma de Células T Periférico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mutação em Linhagem Germinativa , Humanos , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Sequenciamento Completo do Exoma
12.
Hematology Am Soc Hematol Educ Program ; 2018(1): 63-68, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504292

RESUMO

Treatment outcomes for patients with peripheral T-cell lymphomas (PTCLs) and advanced-stage cutaneous T-cell lymphomas (CTCLs) remain poor. The past few years have witnessed an explosion in our understanding of the genetics of these diverse malignancies. Many subtypes harbor highly recurrent mutations, including single-nucleotide variants, insertions/deletions, and chromosomal rearrangements, that affect T-cell receptor signaling, costimulatory molecules, JAK/STAT and phosphatidylinositol 3-kinase pathways, transcription factors, and epigenetic modifiers. An important subset of these mutations is included within commercially available, multigene panels and, in rare circumstances, indicate therapeutic targets. However, current preclinical and clinical evidence suggests that only a minority of mutations identified in TCLs indicate biologic dependence. With a few exceptions that we highlight, mutations identified in TCLs should not be routinely used to select targeted therapies outside of a clinical trial. Participation in trials and publication of both positive and negative results remain the most important mechanisms for improving patient outcomes.


Assuntos
Genômica/métodos , Linfoma de Células T Periférico/genética , Mutação , Humanos , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/genética
13.
Blood Cancer J ; 8(11): 110, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420593

RESUMO

Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes.


Assuntos
Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/mortalidade , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Fator de Transcrição STAT3/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Janus Quinases/metabolismo , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/genética , Terapia de Alvo Molecular , Fosforilação , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Fator de Transcrição STAT3/genética , Resultado do Tratamento
14.
Blood Adv ; 2(19): 2533-2542, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30291111

RESUMO

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) constitutes a heterogeneous category of lymphomas, which do not fit into any of the specifically defined T-cell lymphoma entities. Both the pathogenesis and tumor biology in PTCL-NOS are poorly understood. Protein expression in pretherapeutic PTCL-NOS tumors was analyzed by proteomics. Differentially expressed proteins were compared in 3 distinct scenarios: (A) PTCL-NOS tumor tissue (n = 18) vs benign lymphoid tissue (n = 8), (B) clusters defined by principal component analysis (PCA), and (C) tumors from patients with chemosensitive vs refractory PTCL-NOS. Selected differentially expressed proteins identified by proteomics were correlated with clinico-pathological features and outcome in a larger cohort of patients with PTCL-NOS (n = 87) by immunohistochemistry (IHC). Most proteins with altered expression were identified comparing PTCL-NOS vs benign lymphoid tissue. PCA of the protein profile defined 3 distinct clusters. All benign samples clustered together, whereas PTCL-NOS tumors separated into 2 clusters with different patient overall survival rates (P = .001). Differentially expressed proteins reflected large biological diversity among PTCL-NOS, particularly associated with alterations of "immunological" pathways. The 2 PTCL-NOS subclusters defined by PCA showed disturbance of "stress-related" and "protein metabolic" pathways. α-Enolase 1 (ENO1) was found differentially expressed in all 3 analyses, and high intratumoral ENO1 expression evaluated by IHC correlated with poor outcome (hazard ratio, 2.09; 95% confidence interval, 1.17-3.73; P = .013). High expression of triosephosphate isomerase (TPI1) also showed a tendency to correlate with poor survival (P = .057). In conclusion, proteomic profiling of PTCL-NOS provided evidence of markedly altered protein expression and identified ENO1 as a novel potential prognostic marker.


Assuntos
Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/mortalidade , Proteoma , Proteômica , Aldeído-Desidrogenase Mitocondrial/metabolismo , Biomarcadores Tumorais/metabolismo , Cromatografia Líquida , Biologia Computacional , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Tecido Linfoide/metabolismo , Linfoma de Células T Periférico/genética , Masculino , Fosfopiruvato Hidratase/metabolismo , Prognóstico , Proteômica/métodos , Espectrometria de Massas em Tandem , Proteínas Supressoras de Tumor/metabolismo
15.
Biochem Biophys Res Commun ; 504(4): 749-752, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30217447

RESUMO

Many cancer types carry mutations in protein tyrosine kinase (PTK) and such alterations frequently drive tumor progression. One category is gene translocation of PTKs yielding chimeric proteins with transforming capacity. In this study, we characterized the role of ITK-FER [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with Feline Encephalitis Virus-Related kinase (FER) gene] and ITK-SYK [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with the Spleen Tyrosine Kinase (SYK)] in Peripheral T Cell Lymphoma (PTCL) signaling. We observed an induction of tyrosine phosphorylation events in the presence of both ITK-FER and ITK-SYK. The downstream targets of ITK-FER and ITK-SYK were explored and STAT3 was found to be highly phosphorylated by these fusion kinases. In addition, the CD69 T-cell activation marker was significantly elevated. Apart from tyrosine kinase inhibitors acting directly on the fusions, we believe that drugs acting on downstream targets could serve as alternative cancer therapies for fusion PTKs.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Lectinas Tipo C/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Células COS , Células HEK293 , Humanos , Células Jurkat , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Camundongos , Células NIH 3T3 , Proteínas de Fusão Oncogênica/genética , Fosforilação , Proteínas Tirosina Quinases/genética , Quinase Syk/genética , Quinase Syk/metabolismo , Translocação Genética
16.
Best Pract Res Clin Haematol ; 31(3): 306-314, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30213401

RESUMO

Peripheral T cell lymphoma (PTCL) is a rare subtype of non-Hodgkin lymphoma. PTCLs are heterogeneous in terms of biology, but generally have more aggressive features and poorer outcomes than aggressive B-cell lymphomas when treated with combination chemotherapy. While the best long-term results are still seen with intensive chemotherapeutic approaches, significant progress has been made with molecular profiling identifying genetic drivers of PTCL that could serve as therapeutic targets. Tailoring therapy to different subtypes of PTCL may lead to more individualized approaches with the hope of improved outcomes. In this paper, we review current therapies for treatment of PTCL, newly identified molecular markers, and the role of emerging therapy and novel combinations of existing agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Linfoma de Células T Periférico , Medicina de Precisão/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/terapia
17.
Curr Opin Oncol ; 30(5): 277-284, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30028743

RESUMO

PURPOSE OF REVIEW: Peripheral T-cell lymphomas (PTCLs) represent diverse and aggressive malignancies, with few recent therapeutic improvements. Recent high-throughput genomic studies have revealed the complex mutational landscape of these rare diseases. These novel findings provide the grounds to a more comprehensive classification of these diseases, reflected in the 2017 WHO classification. RECENT FINDINGS: Our review is focused on selected PTCL entities. Angioimmunoblastic T-cell lymphoma and other lymphomas derived from T follicular helper cells feature a rather homogeneous mutational landscape. These neoplasms recapitulate a multistep oncogenic process associating epigenetic deregulation, and second hit mutations affecting the T-cell receptor signaling pathway. This model inferred from comprehensive analyses of patients samples, was confirmed in mouse models. Among ALK-negative anaplastic large-cell lymphomas, translocation-associated subsets are found in both systemic and cutaneous types, and the newly described breast implant-associated type is usually indolent. Extranodal lymphomas of the innate immune system also harbor a combination of mutations affecting different classes of epigenetic modifiers, and mutation-induced activation of the Janus Kinase/signal transduction and activator of transcription pathway. SUMMARY: Understanding of PTCL pathogenesis has substantially improved, and oncogenic events have been identified. The current challenge is to mount efficient therapeutic strategies targeting these aberrations to improve patients' outcome.


Assuntos
Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/etiologia , Humanos , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Transdução de Sinais
18.
Curr Hematol Malig Rep ; 13(4): 318-328, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29951889

RESUMO

PURPOSE OF REVIEW: Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative neoplasms, with at least 29 distinct entities described in current WHO classification. Using present diagnostic approaches, more than a third of PTCL cases cannot be classified, hence designated as PTCL-not otherwise specified (PTCL-NOS). Herein, we summarize the current genomic findings and their role in the molecular pathogenesis in different PTCL entities. RECENT FINDINGS: Gene expression profiling (GEP) studies have identified distinct molecular signatures for accurate diagnosis and elucidated oncogenic pathways enriched in major PTCL entities. Furthermore, genomic characterization has identified recurrent somatic mutations and potential therapeutic targets. Further efforts are underway to develop genetically faithful murine models. GEP studies have identified molecular subgroups of PTCL, characterized by distinct genetic and epigenetic alterations. Understanding the molecular mechanisms of T cell lymphomagenesis using in vivo model will help to reveal novel therapeutic targets.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Células T Periférico , Animais , Humanos , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/terapia , Camundongos , Neoplasias Experimentais/classificação , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Organização Mundial da Saúde
20.
Cancer Sci ; 109(5): 1682-1689, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29493850

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of nodal peripheral T-cell lymphoma (PTCL). Somatic RHOA mutations, most frequently found at the hotspot site c.50G > T, p.Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next-generation sequencing (NGS), droplet digital PCR (ddPCR) and peptide nucleic acid-locked nucleic acid (PNA-LNA) clamp method for detecting the G17V RHOA mutation. G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA-LNA clamp method both detected G17V mutations in 4 samples in addition to those detected with NGS (31 of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance (P < .001). Three other RHOA mutations involving the p.Gly17 position (c.[49G > T;50G > T], p.Gly17Leu in PTCL198; c.[50G > T;51A > C], p.Gly17Val in PTCL216; and c.50G > A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and the PNA-LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had RHOA mutations at the p.Gly17 position. In conclusion, our results suggested that a combination of ddPCR/PNA-LNA clamp methods and NGS are best method to assist the diagnosis of AITL by detecting RHOA mutations at the p.Gly17 position.


Assuntos
Linfadenopatia Imunoblástica/genética , Linfoma de Células T Periférico/genética , Mutação , Oligonucleotídeos/química , Ácidos Nucleicos Peptídicos/química , Reação em Cadeia da Polimerase/métodos , Proteína rhoA de Ligação ao GTP/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfadenopatia Imunoblástica/diagnóstico , Oligonucleotídeos/genética , Ácidos Nucleicos Peptídicos/genética
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