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1.
Br J Haematol ; 168(6): 771-83, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25559471

RESUMO

The currently used 2008 World Health Organization classification recognizes two types of systemic anaplastic large T cell lymphoma according to ALK protein expression in tumour cells. First, the 'anaplastic large cell lymphoma, ALK positive' (ALK(+) ALCL) that is characterized by the presence of ALK gene rearrangements and consequent ALK protein expression, and, second, the 'anaplastic large cell lymphoma, ALK negative' (ALK(-) ALCL) that is a provisional entity lacking ALK protein expression but cannot be distinguished morphologically from ALK(+) ALCL. In this review we summarize the current knowledge on the genetic lesions and biological features that underlie the pathogenesis of ALK(+) and the ALK(-) ALCL and that can lead to the use of targeted anti-cancer agents.


Assuntos
Linfoma Anaplásico de Células Grandes/genética , Quinase do Linfoma Anaplásico , Antineoplásicos/uso terapêutico , Crizotinibe , Humanos , Imunofenotipagem , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/genética , Translocação Genética
2.
Blood ; 122(15): 2683-93, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-24004669

RESUMO

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-) ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma de Células T/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Transplante de Neoplasias , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptores Proteína Tirosina Quinases/genética , Proteína Supressora de Tumor p53/genética , Adulto Jovem
3.
Cancer Sci ; 103(8): 1397-404, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22568409

RESUMO

Mature (peripheral) T-cell and natural killer (NK)-cell lymphomas comprise a series of rather different neoplasms. Based on morphologic, immunophenotypic, genetic, and clinical data, the World Health Organization classification recognizes more than 20 entities or provisional entities. The variable clinical presentations, the objective recognition and pathological stratification, the difficulties regarding treatment, and the hardly predictable response to therapy indicate that the management of these entities requires novel tools. In contrast to B-cell lymphomas or precursor T-cell neoplasms, few recurrent translocations have been identified so far in T-cell non-Hodgkin's and NK-cell lymphomas. Additionally, some of the entities recognized by the World Health Organization classification are very rare and very scarce molecular data are available for T-cell lymphomas. Here, we have reviewed published reports focusing on the genetic lesions and gene expression profiling underlying systemic nodal and extranodal non-cutaneous mature T-cell and NK-cell lymphomas. We also provide a summary of new agents in clinical development and outline some future directions.


Assuntos
Células Matadoras Naturais/patologia , Linfonodos/patologia , Linfoma/genética , Linfócitos T/patologia , Humanos , Linfoma/patologia , Linfoma de Células T/genética
4.
Haematologica ; 97(6): 849-53, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22207685

RESUMO

BACKGROUND: Characterization of the immunoglobulin gene repertoire has improved our understanding of the immunopathogenesis of lymphoid tumors. Early B-lymphocyte precursors of multiple myeloma are known to exist and might be susceptible to antigenic drive. DESIGN AND METHODS: To verify this hypothesis, we collected a database of 345 fully readable multiple myeloma immunoglobulin sequences. We characterized the immunoglobulin repertoire, analyzed the somatic hypermutation load, and investigated for stereotyped receptor clusters. RESULTS: Compared to the normal immunoglobulin repertoire, multiple myeloma displayed only modest differences involving only a few genes, showing that the myeloma immunoglobulin repertoire is the least skewed among mature B-cell tumors. Median somatic hypermutation load was 7.8%; median length of complementarity determining-region 3 was 15.5 amino acids. Clustering analysis showed the absence of myeloma specific clusters and no similarity with published chronic lymphocytic leukemia or lymphoma subsets. CONCLUSIONS: Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor.


Assuntos
Regiões Determinantes de Complementaridade/genética , Genes de Cadeia Pesada de Imunoglobulina/imunologia , Mieloma Múltiplo/genética , Proteínas do Mieloma/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/imunologia , Mineração de Dados , Bases de Dados de Ácidos Nucleicos , Humanos , Família Multigênica/imunologia , Mieloma Múltiplo/imunologia , Proteínas do Mieloma/química , Proteínas do Mieloma/imunologia , Análise de Sequência de DNA , Hipermutação Somática de Imunoglobulina/imunologia
5.
Pest Manag Sci ; 72(7): 1366-72, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26423556

RESUMO

BACKGROUND: The aim of this work was to provide an overview of the prevalence and level of acaricides in beeswax used in Italy in the past 10 years by analysing 1319 beeswax samples processed by the certified laboratory of the Italian Bee Research Institute. RESULTS: The proportion of samples positive to at least one active ingredient decreased between 2005 and 2009 (from 69 to 32%) and then increased again between 2009 and 2014 (from 32 to 91%). This trend is in agreement with reports from beekeepers that the use of synthetic acaricides decreased in the second half of the past decade and increased after the beginning of the colony losses phenomenon. The active ingredient with the greatest overall proportion of positive samples was coumaphos (49%), followed by fluvalinate (38%) and chlorphenvinphos (25%). The indicator for amitraz, 2,4-dimethylphenylformamide (DMPF), was detected in a very small proportion of samples (6%), while residues of cymiazole were never found. CONCLUSIONS: In more than half of the analysed samples, residues of at least one active ingredient were detected. The mean levels of residues of all the considered active ingredients in the positive samples may represent a source of accumulation in beeswax and pose risks to honey bee health. © 2015 Society of Chemical Industry.


Assuntos
Acaricidas/química , Resíduos de Praguicidas/análise , Ceras/química , Clorfenvinfos/química , Cumafos/química , Itália , Nitrilas/química , Piretrinas/química , Inquéritos e Questionários , Tiazóis/química , Toluidinas/química
6.
Oncotarget ; 7(48): 79637-79653, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27793034

RESUMO

Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs.The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies.Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired.These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1.


Assuntos
Acetanilidas/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Concentração Inibidora 50 , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transcriptoma
7.
Leuk Lymphoma ; 56(5): 1223-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25115512

RESUMO

The gene encoding the human BLIMP1, prdm1, is located on chromosome 6q21, a locus frequently deleted in lymphoid tumors. BLIMP1 is able to silence its target genes in a context-dependent manner through different mechanisms. BLIMP1 is expressed in both B and T cells, in which it plays important functions. In B cells, BLIMP1 acts as the master regulator of plasma cell differentiation, repressed by BCL6 and repressing both BCL6 and PAX5. In T cells, BLIMP1 is a critical factor for most terminal effector cell differentiation in both CD4+ and CD8+ T cells. BLIMP1 is frequently inactivated in a variety of lymphomas, including diffuse large B cell lymphomas, Natural Killer cell lymphoma and anaplastic large T cell lymphoma. In this review, we will summarize the role of BLIMP1 in normal cells, focusing on lymphoid cells, and on its function as tumor suppressor gene in lymphomas.


Assuntos
Linfoma de Células B/genética , Linfoma de Células T/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células T/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo
8.
Nat Commun ; 6: 6921, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25891015

RESUMO

The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-ß (TGF-ß) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.


Assuntos
Evolução Biológica , Epigenômica , Linfoma Difuso de Grandes Células B/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Linfoma Difuso de Grandes Células B/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recidiva , Transcriptoma
9.
Clin Cancer Res ; 21(7): 1628-38, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25623213

RESUMO

PURPOSE: In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015. EXPERIMENTAL DESIGN: We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound. RESULTS: OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11. CONCLUSIONS: Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.


Assuntos
Acetanilidas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Linfoma de Células B/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Animais , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Sinergismo Farmacológico , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Cell ; 27(4): 516-32, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25873174

RESUMO

A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Anaplásico de Células Grandes/genética , Fator de Transcrição STAT3/metabolismo , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Janus Quinase 1/genética , Camundongos , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , NF-kappa B/genética , Fosforilação , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , TYK2 Quinase/genética
11.
Mech Ageing Dev ; 133(7): 479-88, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22687638

RESUMO

Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p<0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p=0.620). Acquired Ph-negative cytogenetic abnormalities (p=0.010), lack of complete molecular remission (p=0.016) and age (p=0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p=0.005 for any toxicity, p=0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis.


Assuntos
Senilidade Prematura , Hematopoese , Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Senilidade Prematura/etiologia , Senilidade Prematura/metabolismo , Senilidade Prematura/fisiopatologia , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade
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