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1.
Hum Pathol ; 65: 166-174, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28551327

RESUMO

T-cell transcription factor GATA-3, known to play a role in early T-cell development and in the development of T-cell neoplasms, is expressed at high levels in fetal and adult thymus, as well as in acute leukemias with T-cell differentiation, including T-lymphoblastic leukemia/lymphoma (22/22 cases), early T-cell precursor lymphoblastic leukemia (11/11 cases), and mixed-phenotype acute leukemia, T/myeloid (4/5 cases), but only rarely in acute myeloid leukemia/myeloid sarcoma (1/36 cases), and not in B-lymphoblastic leukemia (0/16 cases). In contrast, T-bet, the other T-cell transcription factor that controls Th1/Th2 T-cell fate, is not expressed to any significant extent in immature thymocytes or in cases of T-lymphoblastic leukemia or acute myeloid leukemia/myeloid sarcoma, but is expressed in most cases (15/16) of B-lymphoblastic leukemia and in mixed-phenotype acute leukemia, B/myeloid. GATA-3-positive acute leukemias with T-cell differentiation were also found to express proto-oncogene C-MYC, in an average of 52% of neoplastic cells, which, along with GATA-3, may contribute to leukemogenesis, as suggested by transgenic mouse models. We conclude that GATA-3 is a sensitive and specific marker for the diagnosis of acute leukemias with T-cell differentiation and may be a useful addition to the panel of immunophenotypic markers for the diagnostic evaluation of acute leukemias.


Assuntos
Biomarcadores Tumorais/análise , Diferenciação Celular , Fator de Transcrição GATA3/análise , Células Precursoras de Linfócitos T/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo , Células Precursoras de Linfócitos T/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Valor Preditivo dos Testes , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-myc/análise , Reprodutibilidade dos Testes , Proteínas com Domínio T/análise , Timócitos/imunologia , Adulto Jovem
2.
Cell Rep ; 17(9): 2367-2381, 2016 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-27880910

RESUMO

Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC.


Assuntos
Proteína BRCA1/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/patologia , Sequência de Aminoácidos , Animais , Proteína BRCA1/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Óxidos N-Cíclicos , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/metabolismo , Dano ao DNA/genética , Reparo do DNA/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Recombinação Homóloga/efeitos dos fármacos , Humanos , Indolizinas , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Compostos de Piridínio/farmacologia , RNA Interferente Pequeno/metabolismo , Transcrição Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cell Rep ; 11(5): 715-26, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25921526

RESUMO

Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , NF-kappa B/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Proteínas de Ligação a DNA/deficiência , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Transdução de Sinais , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Quinase Induzida por NF-kappaB
6.
Am J Surg Pathol ; 35(10): 1531-9, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21921781

RESUMO

Tumor necrosis factor-α-inducible protein-2 (TNFAIP2) is a protein upregulated in cultured cells treated with tumor necrosis factor α (TNF), but its expression in normal and neoplastic tissues remains largely unknown. Here, we use standard immunohistochemical techniques to demonstrate that TNFAIP2 is normally expressed by follicular dendritic cells, interdigitating dendritic cells, and macrophages but not by lymphoid cells in secondary lymphoid tissues. Consistent with this expression pattern, we found strong TNFAIP2 staining of tumor cells in 4 of 4 cases (100%) of follicular dendritic cell sarcoma and in 3 of 3 cases (100%) of histiocytic sarcoma. Although TNFAIP2 is not expressed by the small and intermediate-sized neoplastic B cells comprising follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, or marginal zone lymphoma, we observed strong TNFAIP2 staining of the large, neoplastic cells in 31 of 31 cases (100%) of classical Hodgkin lymphoma, in 12 of 12 cases (100%) of nodular lymphocyte-predominant Hodgkin lymphoma, and in 27 of 31 cases (87%) of primary mediastinal (thymic) large B-cell lymphoma. In contrast, TNFAIP2 was expressed by malignant cells in only 2 of 45 cases (4%) of diffuse large B-cell lymphoma, not otherwise specified, in 2 of 18 cases (11%) of Burkitt lymphoma, and in 1 of 19 cases (5%) of anaplastic large cell lymphoma. Further analysis indicates that TNFAIP2, as a single diagnostic marker, is more sensitive (sensitivity=87%) and specific (specificity=96%) than TRAF1, nuclear cRel, or CD23 for distinguishing the malignant B cells of primary mediastinal (thymic) large B-cell lymphoma from those of its morphologic and immunophenotypic mimic, diffuse large B-cell lymphoma, not otherwise specified. Thus, TNFAIP2 may serve as a useful new marker of dendritic and histiocytic sarcomas, the aberrant expression of which in the malignant cells of classical Hodgkin lymphoma and primary mediastinal (thymic) large B-cell lymphoma serves to distinguish these tumors from other large cell lymphomas in routine clinical practice.


Assuntos
Citocinas/metabolismo , Células Dendríticas/patologia , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Mediastino/diagnóstico , Biomarcadores Tumorais/metabolismo , Células Dendríticas/metabolismo , Diagnóstico Diferencial , Doença de Hodgkin/metabolismo , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Imunoblástico de Células Grandes/diagnóstico , Neoplasias do Mediastino/metabolismo , Baço/metabolismo , Baço/patologia
7.
Nat Med ; 17(7): 875-82, 2011 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-21706030

RESUMO

Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.


Assuntos
Proteína BRCA1/fisiologia , Neoplasias da Mama/tratamento farmacológico , Proteína Quinase CDC2/fisiologia , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Proteína BRCA1/metabolismo , Benzimidazóis/farmacologia , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Transporte/fisiologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Proteínas de Ligação a DNA , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Indazóis/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/fisiopatologia , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiologia , Fosforilação , Proteínas de Ligação a RNA
8.
Clin Cancer Res ; 17(10): 3259-71, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21430070

RESUMO

PURPOSE: Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3. EXPERIMENTAL DESIGN: We evaluated the in vitro antimyeloma activity of AT9283 alone and in combination with lenalidomide and the in vivo efficacy by using a xenograft mouse model of human MM. RESULTS: Our data showed that AT9283 induced cell-growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we observed features consistent with both Aurora kinase A and Aurora kinase B inhibition, such as increase of cells with polyploid DNA content, decrease in phospho-histone H3, and decrease in phospho-Aurora A. Importantly, AT9283 also inhibited STAT3 tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, Aurora kinase A, or Aurora kinase B showed growth inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of MM cell death. In vivo studies showed decreased MM cell growth and prolonged survival in AT9283-treated mice compared with controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in MM cells, even in the presence of bone marrow stromal cells. Enhanced cytotoxicity was associated with increased inhibition of phosphorylated STAT3 and phosphorylated extracellular signal-regulated kinase. CONCLUSIONS: Demonstration of in vitro and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in combination therapy for treating patients with MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Ureia/análogos & derivados , Animais , Aurora Quinase A , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Lenalidomida , Masculino , Camundongos , Camundongos SCID , Modelos Biológicos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Talidomida/administração & dosagem , Resultado do Tratamento , Ureia/administração & dosagem , Ureia/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cancer Cell ; 18(6): 580-9, 2010 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-21156282

RESUMO

Diffuse large B cell lymphoma (DLBCL) comprises disease entities with distinct genetic profiles, including germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCLs. Major differences between these two subtypes include genetic aberrations leading to constitutive NF-κB activation and interference with terminal B cell differentiation through BLIMP1 inactivation, observed in ABC- but not GCB-DLBCL. Using conditional gain-of-function and/or loss-of-function mutagenesis in the mouse, we show that constitutive activation of the canonical NF-κB pathway cooperates with disruption of BLIMP1 in the development of a lymphoma that resembles human ABC-DLBCL. Our work suggests that both NF-κB signaling, as an oncogenic event, and BLIMP1, as a tumor suppressor, play causal roles in the pathogenesis of ABC-DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/etiologia , NF-kappa B/metabolismo , Fatores de Transcrição/fisiologia , Animais , Proliferação de Células , Centro Germinativo/fisiologia , Quinase I-kappa B/genética , Camundongos , Mutação , Plasmócitos/fisiologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Fatores de Transcrição/genética
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