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1.
Am J Hematol ; 98(4): 645-657, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36606708

RESUMO

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.


Assuntos
Linfoma Difuso de Grandes Células B , Recidiva Local de Neoplasia , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Prognóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Mutação , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Proto-Oncogênicas c-bcl-2/genética , Biomarcadores
2.
Curr Oncol Rep ; 22(4): 33, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144513

RESUMO

PURPOSE OF REVIEW: Burkitt's lymphoma and its leukemic form (Burkitt cell acute lymphoblastic leukemia) are a highly aggressive disease. We review the classification, clinical presentation, histology, cytogenetics, and the treatment of the disease. RECENT FINDINGS: Burkitt's lymphoma might be associated with tumor lysis syndrome which is a potentially fatal complication that occurs spontaneously or upon initiation of chemotherapy. Major improvements were made in the treatment of pediatric and adults population using short-course dose-intensive chemotherapy regimens, usually 1 week after a prephase induction. Addition of Rituximab to chemotherapy has become a standard of care. Relapsed/refractory disease has a very poor prognosis and the benefit from autologous/allogeneic hematopoietic stem cell transplant remains uncertain. Rituximab-based short-course dose-intensive chemotherapy is the standard of care of Burkitt's lymphoma even in the immunodeficiency-related form.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Rituximab/administração & dosagem , Antígenos CD20/metabolismo , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 8/genética , Humanos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Translocação Genética
4.
Blood ; 123(13): 2044-53, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24452204

RESUMO

In mantle cell lymphoma (MCL), one allele of the cyclin D1 (Ccnd1) gene is translocated from its normal localization on chromosome 11 to chromosome 14. This is considered as the crucial event in the transformation process of a normal naive B-cell; however, the actual molecular mechanism leading to Ccnd1 activation remains to be deciphered. Using a combination of three-dimensional and immuno-fluorescence in situ hybridization experiments, the radial position of the 2 Ccnd1 alleles was investigated in MCL-derived cell lines and malignant cells from affected patients. The translocated Ccnd1 allele was observed significantly more distant from the nuclear membrane than its nontranslocated counterpart, with a very high proportion of IgH-Ccnd1 chromosomal segments localized next to a nucleolus. These perinucleolar areas were found to contain active RNA polymerase II (PolII) clusters. Nucleoli are rich in nucleolin, a potent transcription factor that we found to bind sites within the Ccnd1 gene specifically in MCL cells and to activate Ccnd1 transcription. We propose that the Ccnd1 transcriptional activation in MCL cells relates to the repositioning of the rearranged IgH-Ccnd1-carrying chromosomal segment in a nuclear territory with abundant nucleolin and active PolII molecules. Similar transforming events could occur in Burkitt and other B-cell lymphomas.


Assuntos
Nucléolo Celular/metabolismo , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ativação Transcricional , Transporte Ativo do Núcleo Celular/fisiologia , Fator de Ligação a CCCTC , Linhagem Celular Tumoral , Ciclina D1/genética , Genes Neoplásicos , Células HeLa , Humanos , Transporte Proteico , Proteínas Repressoras/metabolismo , Nucleolina
7.
Blood ; 118(24): 6310-20, 2011 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-21725049

RESUMO

RUNX1 encodes a DNA-binding α subunit of the core-binding factor, a heterodimeric transcription factor. RUNX1 is a master regulatory gene in hematopoiesis and its disruption is one of the most common aberrations in acute leukemia. Inactivating or dominant-negative mutations in the RUNX1 gene have been also identified in pedigrees of familial platelet disorders with a variable propensity to develop acute myeloid leukemia (FPD/AML). We performed analysis of hematopoiesis from 2 FPD/AML pedigrees with 2 distinct RUNX1 germline mutations, that is, the R139X in a pedigree without AML and the R174Q mutation in a pedigree with AML. Both mutations induced a marked increase in the clonogenic potential of immature CD34(+)CD38(-) progenitors, with some self-renewal capacities observed only for R174Q mutation. This increased proliferation correlated with reduction in the expression of NR4A3, a gene previously implicated in leukemia development. We demonstrated that NR4A3 was a direct target of RUNX1 and that restoration of NR4A3 expression partially reduced the clonogenic potential of patient progenitors. We propose that the down-regulation of NR4A3 in RUNX1-mutated hematopoietic progenitors leads to an increase in the pool of cells susceptible to be hit by secondary leukemic genetic events.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Hematopoese , Leucemia Mieloide Aguda/genética , Deficiência do Pool Plaquetário/genética , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Adolescente , Adulto , Animais , Proliferação de Células , Células Cultivadas , Células Clonais/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Linhagem , Deficiência do Pool Plaquetário/metabolismo , Deficiência do Pool Plaquetário/fisiopatologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Adulto Jovem
8.
Cancer ; 118(20): 5015-25, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22415779

RESUMO

BACKGROUND: Expression of DNA-repair proteins and activated mitogen-activated protein kinases (MAPKs) may differ according to smoking status. The authors investigated whether p38 MAPK activity contributed to the viability of cisplatin in lung cancer cell lines from never or light smokers and to ERCC1 mRNA expression. METHODS: Activated p38 MAPK was tested as a predictor for ERCC1 levels in 117 lung adenocarcinomas. Cell viabilities of NCI-H1975, NCI-H1793, NCI-H1650, and NCI-H1651 cell lines, derived from never or light smokers, were measured after treatment with the p38 MAPK inhibitor SB202190 and cisplatin. The role of p38α (MAPK14) and p38ß (MAPK11) isoforms and ERCC1 was evaluated using RNA interference. RESULTS: ERCC1 protein-level expression was predicted by activated p38 MAPK in lung adenocarcinoma tissues. The p38-specific inhibitor SB202190 strongly decreased cell viability (43%-63%). SB202190 plus cisplatin significantly decreased cell viability in every cell line, including cisplatin-resistant NCI-H1793. Genetic inhibition, targeting both MAPK11 and MAPK14, reduced the viability of the different cell lines: down-regulation of p38ß accounted for most of this effect. Cisplatin's effect was greater after MAPK11 down-regulation for NCI-H1651, and MAPK14 down-regulation for NCI-H1650. In addition, both SB202190 and MAPK11 inhibition reduced excision repair cross-complementing 1 mRNA levels. CONCLUSIONS: Lung cancer cells from never or light smokers rely on p38 MAPK signaling for survival. MAPK11 is involved in that pathway and might contribute to ERCC1 expression. Sensitization to cisplatin can be achieved by pharmacological inhibition of p38 MAPK signaling.


Assuntos
Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Neoplasias Pulmonares/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Interferência de RNA , Transdução de Sinais , Fumar , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
9.
Clin Lymphoma Myeloma Leuk ; 21(4): 257-266.e3, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277223

RESUMO

INTRODUCTION: The role of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is well established in classical Hodgkin lymphoma (HL), where PD-1 blockade demonstrated spectacular efficacy in relapsed/refractory disease. However, little is known about the frequency and cellular distribution of other immune checkpoints in HL samples. PATIENTS AND METHODS: Using immunohistochemistry, we investigated, along with PD-L1 and PD-1, the expression of lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) in 57 biopsy samples of patients with classical HL. RESULTS: Hodgkin and Reed/Sternberg (HRS) cells were strongly positive for PD-L1 in nearly all cases. HRS cells were TIM-3 positive in 36% of samples, whereas LAG-3 was rarely expressed (5.2%). In the microenvironment, PD-1, LAG-3, and TIM-3 were expressed by ≥ 5% of cells in 65%, 98%, and 96% of cases, respectively. T-cell rosettes surrounding HRS cells consisted of CD4+ FoxP3- helper T cells expressing both PD-1 and LAG-3, with a variable expression of TIM-3. CONCLUSION: This study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti-PD-1 antibodies in the treatment of relapsed/refractory HL.


Assuntos
Antígenos CD/genética , Regulação Neoplásica da Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A/genética , Doença de Hodgkin/genética , Adulto , Idoso , Antígenos CD/análise , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/análise , Antígeno B7-H1/genética , Biópsia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/análise , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Células de Reed-Sternberg/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adulto Jovem , Proteína do Gene 3 de Ativação de Linfócitos
10.
Cancer Res ; 67(3): 1145-54, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17283149

RESUMO

Mantle cell lymphoma (MCL) is one of the most frequent of the newly recognized non-Hodgkin's lymphomas. The major problem of MCL therapy is the occurrence of relapse and subsequent resistance to chemotherapy and immunotherapy in virtually all cases. Here, we show that one injection of anti-human transferrin receptor (TfR) monoclonal antibody A24 totally prevented xenografted MCL tumor establishment in nude mice. It also delayed and inhibited tumor progression of established tumors, prolonging mice survival. In vitro, A24 induced up to 85% reduction of MCL cell proliferation (IC(50) = 3.75 nmol/L) independently of antibody aggregation, complement-dependent or antibody-dependent cell-mediated cytotoxicity. A24 induced MCL cell apoptosis through caspase-3 and caspase-9 activation, either alone or synergistically with chemotherapeutic agents. A24 induced TfR endocytosis via the clathrin adaptor protein-2 complex pathway followed by transport to lysosomal compartments. Therefore, A24-based therapies alone or in association with classic chemotherapies could provide a new alternative strategy against MCL, particularly in relapsing cases.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunização Passiva/métodos , Linfoma de Célula do Manto/prevenção & controle , Lisossomos/metabolismo , Receptores da Transferrina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Camundongos , Camundongos Nus , Receptores da Transferrina/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancers (Basel) ; 11(10)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652572

RESUMO

The constitutive expression of CD70 has been described in various haematological and solid tumour types. In addition, the co-expression of its receptor in tumours has been demonstrated, mediating tumour cell proliferation. Although CD70 expression is a prerequisite to enrol patients in solid tumour clinical trials using anti-CD70 immunotherapy, there is currently no standardised test to evaluate CD70 expression. These differences in immunohistochemistry (IHC) protocols make it challenging to compare the expression levels that were obtained in different studies, pointing out the need for one uniform methodology. In this retrospective study, over 600 tumour samples from different solid and haematological malignancies were analysed while using one validated IHC method. CD70 and CD27 expression was demonstrated in a broad range of tumour types. In solid tumours, 43% demonstrated CD70 positivity with the highest degree in renal cell carcinoma (79.5%). Kaposi sarcoma showed no CD70 expression on the tumour cells. In lymphoma samples, 58% demonstrated CD70 positivity. Moreover, the co-expression of CD70 and CD27 was observed in 39% of lymphoma samples. These findings highlight the need to further explore anti-CD70 therapies in a broad range of CD70 expressing tumour types and in doing so, implementing one standardised protocol to define CD70 overexpression to use it as a diagnostic tool.

12.
Clin Cancer Res ; 25(2): 735-746, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348636

RESUMO

PURPOSE: Follicular lymphoma arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exists between the differentiation arrest of follicular lymphoma cells and loss-of-function of CREBBP acetyltransferase.Experimental Design: The study used human primary cells obtained from either follicular lymphoma tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B- and T-cell crosstalk. Responses were assessed by flow cytometry and molecular biology including ChIP-qPCR approaches. RESULTS: Conversely to normal B cells, follicular lymphoma cells are unable to upregulate the transcription repressor, PRDM1, required for plasma cell differentiation. This defect occurs although the follicular lymphoma microenvironment is enriched in the potent inducer of PRDM1 and IL21, highly produced by Tfhs. In follicular lymphoma carrying CREBBP loss-of-function mutations, we found a lack of IL21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Moreover, in these follicular lymphoma cells, pan-HDAC inhibitor, vorinostat, restored their PRDM1 response to IL21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of patients with follicular lymphoma treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell identity genes, mainly PRDM1 and XBP1, which underline the progression of follicular lymphoma B cells in the differentiation process. CONCLUSIONS: Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat patients with follicular lymphoma through the induction of the expression of plasma cell genes.


Assuntos
Proteína de Ligação a CREB/genética , Inibidores de Histona Desacetilases/farmacologia , Interleucinas/metabolismo , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Mutação , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína de Ligação a CREB/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Interleucinas/farmacologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Modelos Biológicos , Gradação de Tumores , Plasmócitos/metabolismo , Plasmócitos/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transcriptoma
13.
Cancer Discov ; 9(6): 796-811, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31018969

RESUMO

The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. SIGNIFICANCE: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.This article is highlighted in the In This Issue feature, p. 681.


Assuntos
Regulação da Expressão Gênica , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/metabolismo , Animais , Azepinas/farmacologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Proliferação de Células , Humanos , Lenalidomida/farmacologia , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Motivos de Nucleotídeos , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transativadores/genética , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Macroglobulinemia de Waldenstrom/diagnóstico
14.
Cancer Chemother Pharmacol ; 61(5): 855-63, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17639395

RESUMO

INTRODUCTION: The cytotoxic activity of the farnesyltranseferase inhibitor R115777 was evaluated in cell lines representative of mantle cell lymphoma (MCL). METHODS: Cell growth, proliferation, and apoptosis were analyzed in four human MCL cell lines (Granta, NCEB, REC, and UPN1) in presence of R115777, alone or in combination with vincristin, doxorubicin, bortezomib, cisplatin and cytarabine. Inhibition of farnesylation was determined by the appearance of prelamin A. The antitumor activity of R115777, administered p.o. at 100, 250 and 500 mg/kg, was determined in vivo in nude mice xenografted with UPN1 cells. RESULTS: R115777 inhibited the growth of MCL cell lines in vitro with inhibitory concentrations ranging between 2 and 15 nM. A fifty percent decrease of cell viability was observed at concentrations comprised between 0.08 and 17 microM. Apoptosis, evaluated by annexin V and activated caspase 3 staining, was induced in all cell lines, in 40 to 71% of the cells depending on the cell lines. In addition, R115777 significantly increased the cytotoxic effect of vincristine, doxorubicin, bortezomib, cisplatin and cytarabine (p=0.001, p=0.016, p=0.006, p=0.014 and p=0.007 respectively). Exposure of MCL cell lines to R115777 during 72 hours resulted in inhibition of protein farnesylation. R115777 administered p.o. twice daily for 8 consecutive days to mice bearing established s.c. UPN1 xenograft displayed cytostatic activity at the 500 mg/kg dosage. CONCLUSION: We have demonstrated that inhibition of farnesyltransferase by R115777 was associated with growth inhibition and apoptosis of MCL cell lines in vitro and tumor xenograft stability in vivo.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Quinolonas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Farnesiltranstransferase/antagonistas & inibidores , Feminino , Humanos , Lamina Tipo A , Camundongos , Camundongos Nus , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Precursores de Proteínas/efeitos dos fármacos , Precursores de Proteínas/metabolismo , Quinolonas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Biother Radiopharm ; 22(5): 665-71, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17979569

RESUMO

PURPOSE: Radioimmunotherapy with anti-CD20 antibodies (Abs) labeled with beta-emitters is now used in the treatment of non-Hodgkin's lymphoma (NHL). Because (90)Y is a pure beta-emitter, no direct image of its distribution can be obtained in humans. In this paper, we present in this study imaging data of (90)Y-Ab distribution in human-mantle-cell lymphoma within a mouse model. Describing the actual distribution of the radionuclide at the level of particles range may have important impact on patient dosimetry and therapy treatment planning. EXPERIMENTAL DESIGN: NOD/SCID mice were grafted with a human NHL cell line that involves the bone marrow. The mice were treated with (90)Y-ibritumomab tiuxetan (Zevalin); Schering AG, Germany) and sacrificed 2 hours after Zevalin administration. Tissue sections were then prepared and viewed under conventional microscopy. The distribution of the radioactivity in mouse femur was determined by using digital autoradiography and subsequently correlated with immunohistochemical results. RESULTS: Various extent of bone marrow infiltration was investigated and found to be reproducible. Zevalin uptake was heterogeneous within the bone marrow. However, unspecific mouse monoclonal uptake by accessory myeloid cells gave nonspecific background radioactivity. Treating mice with an irrelevant mouse IgG1 monoclonal antibody (mAb) before Zevalin injection controlled this unspecific uptake, and images were strongly correlated with bone marrow infiltration on histologic analysis. CONCLUSIONS: Our model was reproducible, and allows for the study of various bone marrow involvement with good sensitivity. We demonstrated that imaging of the beta-emitter was possible with good image quality and that (90)Y-Zevalin is distributed heterogeneously within bone marrow. These data suggest that detailed pharmacokinetics may be developed with this model.


Assuntos
Anticorpos Monoclonais/farmacocinética , Medula Óssea/metabolismo , Linfoma não Hodgkin/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Autorradiografia , Sítios de Ligação de Anticorpos/imunologia , Medula Óssea/patologia , Linhagem Celular Tumoral , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Fêmur/patologia , Humanos , Imunoglobulina G/imunologia , Imuno-Histoquímica , Imunotoxinas/imunologia , Imunotoxinas/farmacocinética , Imunotoxinas/uso terapêutico , Antígenos Comuns de Leucócito/análise , Antígenos Comuns de Leucócito/metabolismo , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/radioterapia , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/radioterapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neprilisina/imunologia , Radioimunoterapia/métodos , Cintilografia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Gene ; 580(2): 134-143, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26774800

RESUMO

Mantle cell lymphoma (MCL) is a rare lymphoma caused by the t(11:14) juxtaposing the cyclin D1 (CCND1) locus on chromosome 11 and the immunoglobulin heavy chain (IgH) locus on chromosome 14. Several new treatments are proposed for MCL, including histone deacetylase inhibitors (HDACi). We have studied gene expression and chromatin organization in the translocated 11q13 locus in MCL cells as compared to lymphoblastoid cell lines as well as the effect of HDACi abexinostat on chromatin organization and gene expression in the 11q13 locus. We have identified a cluster of genes overexpressed in the translocation region on chromosome 11 in MCL cells. Abexinostat provokes a genome-wide disaggregation of heterochromatin. The genes upregulated after the t(11;14) translocation react to the HDACi treatment by increasing their expression, but their gene promoters do not show significant alterations in H3K9Ac and H3K9me2 levels in abexinostat-treated cells.


Assuntos
Linfócitos B/efeitos dos fármacos , Benzofuranos/farmacologia , Cromatina/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Linfoma de Célula do Manto/genética , Transcrição Gênica/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Translocação Genética/genética
17.
PLoS One ; 8(9): e73993, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24069261

RESUMO

PURPOSE: We designed a gene profiling experiment to identify genes involved in secondary drug resistance in mantle cell lymphomas (MCL). EXPERIMENTAL DESIGN: We obtained paired tissue samples collected from the same patients before treatment and after relapse or progression. Variations in gene expression between the 2 samples were estimated for 5 patients. For each gene, the mean variation was estimated for patients with a refractory primary tumor and for responders who developed secondary drug resistance. Nine genes of interest were selected on the basis of the magnitude and statistical significance of the variation of expression in responders and non-responders. RESULTS: BMP7 was the only one with significantly increased expression at relapse in patients who developed secondary resistance. Validation of BMP7 as a key gene involved in secondary resistance was performed using cultures of cell line. Incubation of BMP7 with MCL cell lines increased their resistance to bortezomib and cytarabine, while inhibition of BMP7 expression by siRNA correlated with increased cell death linked to drug application. CONCLUSION: Variations in gene expression after treatment point out BMP7 as a key gene involved in secondary resistance in mantle cell lymphoma.


Assuntos
Proteína Morfogenética Óssea 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Linfoma de Célula do Manto/genética , Adulto , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sequência de Bases , Proteína Morfogenética Óssea 7/química , Proteína Morfogenética Óssea 7/metabolismo , Ácidos Borônicos/farmacologia , Ácidos Borônicos/toxicidade , Bortezomib , Linhagem Celular Tumoral , Ilhas de CpG , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estadiamento de Neoplasias , Pirazinas/farmacologia , Pirazinas/toxicidade , Interferência de RNA , Recidiva , Resultado do Tratamento
18.
Expert Rev Anticancer Ther ; 12(9): 1205-15, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23098120

RESUMO

The characterization of the mantle cell lymphoma (MCL) entity had a major impact on patient management and has played a profound role in improving therapy. Although the prognosis is improving in MCL, there is no definitive proof that the therapies currently available will lead to cure. Few randomized studies have been conducted in MCL patients. In young patients, initial intensive therapy with high-dose cytarabine followed by high-dose chemotherapy and hematopoietic stem cell reinfusion has resulted in prolonged progression-free survival. In elderly subjects, who always represent a more heterogeneous group of patients, there is no consensus concerning which drugs can be used during induction chemotherapy. New drugs have essentially been evaluated in patients with recurrent disease or refractory to first-line regimens. Recently, two of them (bortezomib and temsirolimus) with different modes of action were registered in MCL. Targeted therapies are also being investigated extensively in MCL and are yielding interesting activities.


Assuntos
Citarabina/farmacologia , Drogas em Investigação/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Fatores Etários , Idoso , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Ácidos Borônicos/farmacologia , Bortezomib , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Humanos , Linfoma de Célula do Manto/metabolismo , Prognóstico , Pirazinas/farmacologia , Recidiva , Terapia de Salvação/métodos , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Análise de Sobrevida , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Conduta Expectante/métodos
19.
Stem Cells ; 24(8): 1937-45, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16690781

RESUMO

The Oct4 transcription factor is essential for the self-renewal and pluripotency of embryonic stem cells (ESCs). Oct4 level also controls the fate of ESCs. We analyzed the effects of Oct4 overproduction on the hematopoietic differentiation of ESCs. Oct4 was introduced into ESCs via a bicistronic retroviral vector, and cells were selected on the basis of Oct4 production, with Oct4(+) and Oct4(2+) displaying twofold and three- to fourfold overproduction, respectively. Oct4 overproduction inhibited hematopoietic differentiation in a dose-dependent manner, after the induction of such differentiation by the formation of day 6 embryoid bodies (EB6). This effect resulted from defective EB6 formation rather than from defective hematopoietic differentiation. In contrast, when hematopoiesis was induced by the formation of blast colonies, the effects of Oct4 depended on the level of overproduction: twofold overproduction increased hematopoietic differentiation, whereas higher levels of overproduction markedly inhibited hematopoietic development. This increase or maintenance of Oct4 levels appears to alter the kinetics and pattern of mesoderm commitment, thereby modifying hemangioblast generation. These results demonstrate that Oct4 acts as a master regulator of ESC differentiation.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Hematopoéticas/citologia , Mesoderma/fisiologia , Fator 3 de Transcrição de Octâmero/genética , Animais , Linhagem Celular , Células-Tronco Embrionárias/citologia , Perfilação da Expressão Gênica , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Células-Tronco Hematopoéticas/fisiologia , Mesoderma/citologia , Camundongos , Fator 3 de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
20.
Blood ; 108(5): 1551-4, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16684963

RESUMO

The biologic hallmark of polycythemia vera (PV) is the formation of endogenous erythroid colonies (EECs) with an erythropoietin-independent differentiation. Recently, it has been shown that an activating mutation of JAK2 (V617F) was at the origin of PV. In this work, we studied whether the STAT5/Bcl-xL pathway could be responsible for EEC formation. A constitutively active form of STAT5 was transduced into human erythroid progenitors and induced an erythropoietin-independent terminal differentiation and EEC formation. Furthermore, Bcl-xL overexpression in erythroid progenitors was also able to induce erythroid colonies despite the absence of erythropoietin. Conversely, siRNA-mediated STAT5 and Bcl-xL knock-down in human erythroid progenitors inhibited colony-forming unit-erythroid (CFU-E) formation in the presence of Epo. Altogether, these results demonstrate that a sustained level of the sole Bcl-xL is capable of giving rise to Epo-independent erythroid colony formation and suggest that, in PV patients, JAK2(V617F) may induce EEC via the STAT5/Bcl-xL pathway.


Assuntos
Eritropoese/fisiologia , Fator de Transcrição STAT5/metabolismo , Células-Tronco/citologia , Células-Tronco/fisiologia , Proteína bcl-X/metabolismo , Diferenciação Celular , Ensaio de Unidades Formadoras de Colônias , Eritropoetina/fisiologia , Deleção de Genes , Humanos , Policitemia Vera/sangue , RNA Interferente Pequeno/genética , Fator de Transcrição STAT5/genética , Proteína bcl-X/genética
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