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1.
Leukemia ; 26(10): 2277-85, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22475873

RESUMO

Sporadic Burkitt lymphoma (sBL) is a rapidly growing B-cell non-Hodgkin's lymphoma whose treatment requires highly aggressive therapies that often result severely toxic. Identification of proteins whose expression or function is deregulated in sBL and play a role in its formation could facilitate development of less toxic therapies. We have previously shown that E2F1 expression is deregulated in sBL. We have now investigated the mechanisms underlying E2F1 deregulation and found that the E2F sites in its promoter fail to repress its transcriptional activity in BL cells and that the transcriptional repressor E2F4 barely interacts with these sites. We also have found that E2F4 protein levels, but not those of its mRNA, are reduced in sBL cell lines relative to immortal B-cell lines. E2F4 protein expression is also decreased in 24 of 26 sBL tumor samples from patients compared with control tissues. Our data demonstrate that enforced E2F4 expression in BL cells not only diminishes E2F1 levels, but also reduces selectively the tumorigenic properties and proliferation of BL cells, while increasing their accumulation in G(2)/M. Our results therefore point to E2F4 as a target for developing novel and less toxic treatments for sBL.


Assuntos
Linfoma de Burkitt/etiologia , Transformação Celular Neoplásica , Fator de Transcrição E2F4/fisiologia , Animais , Linfoma de Burkitt/química , Divisão Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/química , Proteína Substrato Associada a Crk/fisiologia , Fator de Transcrição E2F1/análise , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F4/análise , Feminino , Fase G2 , Humanos , Camundongos , Células NIH 3T3 , Regiões Promotoras Genéticas
3.
Leukemia ; 23(10): 1847-57, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19474799

RESUMO

Clinical and biological studies on nodal marginal zone lymphoma (NMZL) are hampered by the lack of specific diagnostic markers and the low reproducibility of this diagnosis. A comparative expression-profiling study has shown a set of markers to be differentially expressed in NMZL compared with follicular lymphoma (FL), including myeloid cell nuclear differentiation antigen (MNDA), a nuclear protein expressed by myeloid cells and a subset of B-cells. The aim of this study was to characterize the expression of MNDA in normal and reactive human tissue, and in a large series of non-Hodgkin's B-cell lymphomas, with particular emphasis on NMZL and FL. Our results showed that MNDA is expressed in normal tissue by a subset of the marginal zone B cells. They also showed MNDA expression in subgroups of chronic lymphocytic leukemia, mantle-cell lymphoma, and diffuse large B-cell lymphoma, but MNDA was especially expressed by lymphomas derived from the marginal zone, such as mucosa-associated lymphoid-tissue lymphoma, splenic marginal-zone lymphoma and NMZL. MNDA expression was rarely observed in FL, a characteristic that is of potential value in distinguishing between NMZL and FL. MNDA expression is thus a useful tool for the recognition of NMZL.


Assuntos
Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores Tumorais/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma Folicular/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Biomarcadores Tumorais/genética , Western Blotting , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina G/imunologia , Hibridização in Situ Fluorescente , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Análise Serial de Tecidos , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
4.
Cancer Lett ; 230(1): 141-8, 2005 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-16253770

RESUMO

In spite of much effort, no good markers have yet been found for predicting prognosis or response to therapy in advanced head and neck squamous cell carcinoma (HNSCCs) patients. beta-catenin, a protein involved in the cytoskeleton, cell-cell adhesion and gene transcription, is a factor associated with tumour progression. Recently, an interaction has been reported between beta-catenin, and NF-kappaB coupled with an inverse association of beta-catenin, and FAS (CD95/APO-1) protein expression in breast and colorectal tumours. To confirm these observations and to test their clinical impact in HNSCCs we have evaluated the expression of beta-catenin, NF-kappaB and FAS proteins. We used tissue microarrays to simultaneously analyse the levels of these proteins immunohistochemically in 118 HNSCCs. Among the 113 tumours evaluable for beta-catenin, increased and decreased levels were detected in 41 (36%) and 62 (55%) of the tumours, respectively. beta-catenin, protein staining was mainly membranous but 10 tumours (9%) showed the clear presence of protein in the cytoplasm, and none in the nucleus. Moreover, 81% of the tumours had decreased FAS protein expression, indicating that loss of FAS protein is a common feature of HNSCCs. Abnormal or nuclear NF-kappaB staining was observed in 24% of the tumours. No association was detected between the expression levels of the proteins evaluated. Regarding clinical associations, tumours from the hypopharynx had significantly lower levels of beta-catenin expression than those from other locations (P<0.05). Moreover, our data revealed that patients whose tumours had low levels of beta-catenin protein expression had decreased survival probability (24.8 months vs. NR, P=0.03) and reduced response to therapy (15.4 vs. 43 months; P=0.01) compared with patients whose tumours had high levels of beta-catenin. Taken together, our observations indicate that beta-catenin, NF-kappaB and FAS expression are independent events during HNSCC development and that levels of beta-catenin protein may identify subsets of advanced HNSCCs patients with different prognosis and response to therapy capabilities.


Assuntos
Carcinoma de Células Escamosas/fisiopatologia , Neoplasias de Cabeça e Pescoço/fisiopatologia , NF-kappa B/biossíntese , Receptores do Fator de Necrose Tumoral/biossíntese , beta Catenina/biossíntese , Biomarcadores Tumorais/análise , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , NF-kappa B/análise , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Receptores do Fator de Necrose Tumoral/análise , Análise de Sobrevida , beta Catenina/análise , Receptor fas
5.
Histopathology ; 41(3): 216-29, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12207783

RESUMO

AIMS: An accurate diagnosis of T-cell/histiocyte-rich large B-cell lymphoma needs to take into consideration those forms of Hodgkin's lymphoma also characterized by a predominance of small lymphocytes and histiocytes, i.e. nodular lymphocyte predominance Hodgkin's lymphoma and lymphocyte-rich classical Hodgkin's lymphoma. We have studied the clinical, phenotypic and genetic features of a series of 12 cases of T-cell/histiocyte-rich large B-cell lymphoma along with 18 cases of Hodgkin's lymphoma for comparative purposes. METHODS AND RESULTS: Of the Hodgkin's lymphoma cases, there were 11 lymphocyte predominance type and seven classic type. T-cell/histiocyte-rich large B-cell lymphomas presented usually in advanced stages (III or IV in 11/12 cases), frequently with 'B' symptoms (6/9 cases), and followed a more aggressive course than Hodgkin's lymphoma (4/8 patients died due to the tumour in T-cell/histiocyte-rich large B-cell lymphoma versus 0/15 in Hodgkin's lymphoma). T-cell/histiocyte-rich large B-cell lymphoma cases showed diffuse effacement of the nodal architecture by a proliferation of scattered large atypical B-cells obscured by a background of small T-lymphocytes (more CD8+, TIA1+ than CD57+). Five cases showed also a prominent histiocytic component. The large B-cells expressed CD45 and often EMA (6/10 cases). On the other hand, CD 30, CD15 and latent infection by Epstein-Barr virus (EBV) were generally lacking. bc l6 and CD10 were, respectively, detected in 6/6 and 1/5 cases. Conventional polymerase chain reaction (PCR) showed monoclonal immunoglobulin heavy chain (IgH) gene rearrangements in all T-cell/histiocyte-rich large B-cell lymphomas studied (5/5), but did not detect any case with t(14;18) involving the major breakpoint region (0/4). CONCLUSIONS: The differential diagnosis of T-cell/histiocyte-rich large B-cell lymphoma from Hodgkin's lymphoma is facilitated by the integration of different immunophenotypic, molecular and clinical findings. T-cell/histiocyte-rich large B-cell lymphoma is a monoclonal neoplasm of bc l6+ B-cells with a phenotypic profile similar to lymphocyte predominance Hodgkin's lymphoma, suggesting a germinal centre origin and a possible relation to this disease. Therefore, in order to distinguish it from lymphocyte predominance Hodgkin's lymphoma, characterization of the reactive background, IgH gene rearrangement studies by conventional PCR and clinical features are more useful. In contrast, T-cell/histiocyte-rich large B-cell lymphoma can be distinguished from classical Hodgkin's lymphoma thanks to the presence of monoclonal IgH rearrangement and the CD 30-CD15-CD45+EMA+ immunophenotypic profile of the neoplastic cells in T-cell/histiocyte-rich large B-cell lymphoma.


Assuntos
Histiócitos/patologia , Doença de Hodgkin/patologia , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Linfócitos T/patologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Histiócitos/metabolismo , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Linfócitos T/metabolismo
6.
Am J Pathol ; 158(4): 1363-9, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11290554

RESUMO

Monocytoid B cells (MBCs) are a subset of B cells that may be recognized in several reactive and tumoral lymph node conditions, including toxoplasmic lymphadenitis, infectious mononucleosis, and Hodgkin's lymphoma. Although this is a commonly observed cell population, which has even given its name to a type of lymphoma, MBC lymphoma, scarcely any information is available about the function and characteristics of this cell type. A relationship with marginal zone (MZ) B lymphocytes has been claimed for MBCs, but this has not yet been fully proven. Indeed, specific markers for MBCs are still lacking, which has made it difficult to analyze their relationship with other B cell subpopulations and confirm the existence of tumors deriving from this B cell subset. We used a panel of cell cycle markers to explore the characteristics of MBCs and their relationship with MZ B cells, nodal MZ lymphoma, and splenic MZ lymphoma. We therefore compared the phenotypic profile of MBCs in different conditions with normal MZ B cells within the spleen and mesenteric lymph nodes, with a group of seven cases of nodal MZ/MBC lymphoma and another group of five cases of splenic MZ lymphoma. MBCs were mainly in the G(0) to G(1) phases, as deduced from the presence of a proportion of between 10 and 35% Ki67-positive cells, whereas very low expression was observed with cyclin A and cyclin B staining. Nests of MBCs were clearly labeled by the expression of p21(WAF1), a cyclin-dependent kinase inhibitor (CKI), rarely detectable in benign lymphocytes, and by cyclin E. Basically all MBCs were bcl-2-negative, and high cyclin D2 and cyclin D3 were also detected in these cells, at proportions and intensities above expected levels, when the percentage of proliferating cells was taken into account. p27(KIP1) expression was characterized by homogeneous reactivity, higher than that observed in other B cell populations with a relatively high-growth fraction. Immunoglobulin staining showed undetectable light and heavy chains. However, splenic MZ cells, nodal MZ lymphoma, and splenic MZ lymphoma showed a distinct expression of IgM and bcl-2, with high p27 (KIP1) nuclear expression and undetectable or low levels of cyclin A, B, E, or D, or p21(WAF1) expression. The data from this study show an unexpected immunophenotype in MBCs, different from the one observed in splenic and lymph node MZ B cells. This suggests that either MBCs are a unique B cell population from a distinct cell lineage, or if related to MZ cells, they would represent a definite differentiation stage characterized by a distinctive immunophenotype. They also show so-called MZ/MBC lymphoma to be more closely related to lymph node and splenic MZ B cells, as they do not share the most distinctive features of MBCs.


Assuntos
Linfócitos B/fisiologia , Linfoma de Células B/genética , Linfoma de Células B/patologia , Monócitos/fisiologia , Humanos , Imunofenotipagem , Linfonodos/citologia , Mesentério , Fenótipo , Valores de Referência , Baço/citologia , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologia
7.
Histopathology ; 35(2): 144-9, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10460659

RESUMO

AIMS: Overexpression of CD44v6 in colon crypt epithelial cells has been suggested to have diagnostic potential in differentiating ulcerative colitis from other forms of colon inflammation, including Crohn's disease. Our aim was to determine the value of CD44v6 expression in inflammatory bowel disease (IBD) and to look for possible associations between CD44v6 expression and activity of this disease. METHODS AND RESULTS: CD44v6 expression was studied using immunohistochemical techniques in 100 surgical and endoscopic colon samples of ulcerative colitis (n = 71) and Crohn's disease (n = 29), and in every case disease activity was studied by endoscopy and microscopic examination. Fifty-five of 71 (77.5%) samples of ulcerative colitis showed monoclonal antibody 2F10 stained colon epithelium, as did 16 of 29 (55.2%) samples of Crohn's disease. CD44v6 was detected in 88.2% (15 of 17) of cases of IBD with severe disease activity and in 100% of eight cases of severe ulcerative colitis. Our study showed a strong association between CD44v6 expression and the activity of IBD (P = 0.007). CONCLUSIONS: CD44v6 expression in IBD is significantly associated with activity detected by means of endoscopy and pathological features. Our data suggest that CD44v6 expression may have some usefulness in conjunction with other factors as a means of evaluating the disease activity. Moreover, CD44v6 expression was higher in ulcerative colitis than Crohn's disease (P = 0.02), although this does not confirm the utility of monoclonal antibody 2F10 in differential diagnosis between ulcerative colitis and Crohn's disease, as there was a notable percentage of positive samples of Crohn's disease.


Assuntos
Colite Ulcerativa/metabolismo , Colo/metabolismo , Doença de Crohn/metabolismo , Glicoproteínas/metabolismo , Receptores de Hialuronatos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Colo/patologia , Colo/cirurgia , Colonoscopia , Doença de Crohn/patologia , Doença de Crohn/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Técnicas Imunoenzimáticas , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade
8.
Blood ; 94(2): 765-72, 1999 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10397744

RESUMO

p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt's lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt's cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.


Assuntos
Proteínas de Ciclo Celular , Ciclinas/biossíntese , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas de Neoplasias/biossíntese , Células-Tronco Neoplásicas/metabolismo , Proteínas Supressoras de Tumor , Linfoma de Burkitt/patologia , Ciclo Celular , Ciclina D3 , Inibidor de Quinase Dependente de Ciclina p27 , Ciclinas/genética , Progressão da Doença , Células-Tronco de Carcinoma Embrionário , Centro Germinativo/citologia , Humanos , Linfonodos/patologia , Linfoma de Células B/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Tonsila Palatina/patologia , Fase S , Células Tumorais Cultivadas
9.
Lab Invest ; 79(12): 1453-9, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10616196

RESUMO

p16 protein binds and inactivates cyclin D-CDK4/6 complexes, stopping the cell cycle at the G1/S boundary. Loss of p16 expression is found frequently in human cancer tissues, often resulting from allelic loss or promoter region hypermethylation in non-Hodgkin's lymphomas. Hodgkin's disease has been shown to be a monoclonal neoplasm of B-cells in which a majority of cells are cycling. In the attempt to identify hypothetical CDK inhibitor inactivation that could explain the accumulation of proliferating cells, we decided to focus on the p16INK4A gene. To determine whether inactivation of this gene is implicated in the development of Hodgkin's disease, we immunostained 40 cases with a monoclonal antibody for the p16 protein. At the same time, we used a methylation-specific PCR technique to determine the methylation status of exon 1 of the p16INK4A gene in 23 cases in this series. Loss of p16 expression was found in 30 of 37 cases (absence of expression in most Hodgkin's/Reed-Sternberg cells, with a normal scattered pattern of p16 expression in the reactive background). Only seven samples showed nuclear p16 expression in a significant proportion of large tumoral cells. In agreement with this finding, hypermethylation of p16INK4A gene was found in 14 of 23 cases by PCR. All the p16 cases found positive by immunohistochemistry also showed unmethylated DNA. These results show that loss of p16 protein expression is usually observed in Hodgkin's/Reed-Sternberg cells in Hodgkin's disease, frequently associated with p16INK4A gene hypermethylation. The high frequency of abnormal methylation found in this study suggests that this genetic event may play an important role in the pathogenesis of the disease.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Genes p16 , Doença de Hodgkin/genética , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase , Células Tumorais Cultivadas
10.
Am J Pathol ; 153(3): 887-97, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9736037

RESUMO

The CDKN2A gene located on chromosome region 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16/INK4A, a negative cell cycle regulator. We analyzed p16/INK4A expression in different types of non-Hodgkin's lymphoma to determine whether the absence of this protein is involved in lymphomagenesis, while also trying to characterize the genetic events underlying this p16/INK4A loss. To this end, we investigated the levels of p16/INK4A protein using immunohistochemical techniques in 153 cases of non-Hodgkin's lymphoma, using as reference the levels found in reactive lymphoid tissue. The existence of gene mutation, CpG island methylation, and allelic loss were investigated in a subset of 26 cases, using single-strand conformational polymorphism and direct sequencing, Southern Blot, polymerase chain reaction, and microsatellite analysis, respectively. Loss of p16/INK4A expression was detected in 41 of the 112 non-Hodgkin's lymphomas studied (37%), all of which corresponded to high-grade tumors. This loss of p16/INK4A was found more frequently in cases showing tumor progression from mucosa-associated lymphoid tissue low-grade lymphomas (31 of 37) or follicular lymphomas (4 of 4) into diffuse large B-cell lymphomas. Analysis of the status of the p16/INK4A gene showed different genetic alterations (methylation of the 5'-CpG island of the p16/INK4A gene, 6 of 23 cases; allelic loss at 9p21, 3 of 16 cases; and nonsense mutation, 1 of 26 cases). In all cases, these events were associated with loss of the p16/INK4A protein. No case that preserved protein expression contained any genetic change. Our results demonstrate that p16/INK4A loss of expression contributes to tumor progression in lymphomas. The most frequent genetic alterations found were 5'-CpG island methylation and allelic loss.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Células Cultivadas , Cromossomos Humanos Par 9/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Primers do DNA/química , Progressão da Doença , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Perda de Heterozigosidade , Linfoma não Hodgkin/genética , Metilação , Microscopia Confocal , Reação em Cadeia da Polimerase , Proteínas/genética , Proteínas/metabolismo , Proteína Supressora de Tumor p14ARF
11.
J Clin Pathol ; 50(8): 645-53, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9301547

RESUMO

AIMS: To determine the expression of p21WAF1/CIP1 in relation to the expression of Ki67 and p53 in various normal adult and fetal tissues, and to investigate its distribution throughout the cell cycle. METHODS: The expression of p21WAF1/CIP1 in relation to Ki67 and p53 was analysed in adult and fetal tissues using immunohistochemical techniques. Heat induced epitope retrieval techniques were used to characterise the presence of p21WAF1/CIP1 in different tissues, as well as to detect its distribution throughout the cell cycle. In addition, flow cytometry and western blotting were used to test whether the level of p21WAF1/CIP1 expression varied at different phases of the cell cycle in phytohaemagglutinin (PHA) stimulated lymphocytes. RESULTS: p21WAF1/CIP1 expression varied from one tissue to another, and it was restricted mainly to the squamous and glandular epithelium, where it appeared in association with p53. Human tissues in which p21WAF1/CIP1 was found showed a mutually exclusive topographical sequential expression between p21WAF1/CIP1 and Ki67. This was confirmed by double labelling studies, which showed that p21WAF1/CIP1 positive cells were in the G0 phase. Unlike these findings of a decline in p21WAF1/CIP1 expression after the G0 phase, PHA stimulated lymphocytes showed a level of p21WAF1/CIP1 expression that rose as the cell progressed through the cell cycle. CONCLUSIONS: The analysis of p21WAF1/CIP1 expression in relation to the status of p53 should take into account the existence of variable p21WAF1/CIP1 expression in different tissues. This could provide an explanation for the varying frequency of p53 mutations in tumours of different cellular origin. In tissues characterised by regular p21WAF1/CIP1 expression, it appears in a pattern that is consistent with the proposed role of this inhibitor of cyclin dependent kinases in cell cycle arrest-that of inducing cell differentiation. The conflicting results of in vivo and in vitro studies could support the hypothesis that microenvironmental conditions may influence the location of p21WAF1/CIP1 in different phases of the cell cycle.


Assuntos
Ciclinas/metabolismo , Inibidores Enzimáticos/metabolismo , Feto/metabolismo , Antígeno Ki-67/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Western Blotting , Ciclo Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p21 , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Ativação Linfocitária/fisiologia , Masculino , Fito-Hemaglutininas/imunologia
12.
Am J Pathol ; 151(1): 151-60, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9212741

RESUMO

Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDKIs). p27KIP1, which has a high degree of similarity with p21WAF1, is a general CDKI thought to be involved in G1 arrest in response to agents that inhibit cell cycle progression. The aims of this study were 1) to establish the pattern of expression of p27KIP1 protein in nontumor lymphoid tissue, 2) to determine whether p27KIP1 is involved in lymphomagenesis, and 3) to address the possible relationship between p27KIP1 and p21WAF1 expression in reactive and tumor lymphoid tissue. p27KIP1 protein was found to be mainly present in quiescent lymphocytes in reactive lymphoid tissue as well as in peripheral blood lymphocytes, with an inverse expression for p27KIP1 and Ki-67 proteins. The same p27KIP1 expression pattern was observed in lymphomas, independently of histological type; small resting cells were p27KIP1 positive, and large proliferating cells were p27KIP1 negative. Therefore, tumors with a low proliferative index were mostly positive, whereas tumors characterized by a higher growth fraction bad low p27KIP1 protein levels. An unexpected finding was the existence of a group of six cases of high-grade lymphomas (three diffuse large B-cell lymphomas and three Burkitt's lymphomas) with homogeneously strong staining for p27KIP1 protein. All 6 of these cases belong to a group of 28 cases characterized by blockage of the p53 tumor suppressor pathway, as determined by genetic (p53 mutation) or immunophenotypic studies (p53+/p21-). p27KIP1 expression was not seen in any case of aggressive non-Hodgkin's lymphoma with an intact p53 pathway. The results indicate that p27KIP1 is down-regulated in lymphomas with a high proliferative index, although it is highly expressed in high-grade lymphomas with defects in the p53 pathway.


Assuntos
Proteínas de Ciclo Celular , Quinases Ciclina-Dependentes/antagonistas & inibidores , Tecido Linfoide/metabolismo , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Supressoras de Tumor , Divisão Celular , Inibidor de Quinase Dependente de Ciclina p27 , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Tecido Linfoide/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia
13.
J Pathol ; 177(1): 27-34, 1995 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7472776

RESUMO

MDM2 and p53 immunohistochemical protein expression was analysed in lymphocytes and in reactive and neoplastic lymphoid tissue. Phytohaemagglutinin (PHA)-stimulated lymphocytes displayed MDM2 and p53 co-expression. In 8 of 8 tonsils, 24 of 24 Hodgkin's disease (HD), and 10 of 24 high-grade non-Hodgkin's lymphoma (HG-NHL) specimens, MDM2 paralleled p53 nuclear expression in non-tumour and tumour cells. The number of positive cells was greater and the staining intensity was stronger for p53 than for MDM2. In another nine of the 24 HG-NHL cases studied, dissociated expression was observed, with high p53 expression and very low or absent MDM2 expression. In five cases, both MDM2 and p53 were negative. The eight low-grade NHL (LG-NHL) cases were also MDM2- and p53-negative. MDM2 and p53 expression in PHA-activated lymphocytes and reactive lymphoid tissue is probably an expression of opposing biological signals regulating cell proliferation. Parallel MDM2 and p53 expression in all HD and in 10 out of 24 HG/NHL cases may indicate that this growth suppressive pathway is maintained in those cases. However, dissociated MDM2/p53 expression (nine cases) and the absence of expression of both proteins (five cases) may represent examples of deregulation of this growth control pathway. These findings are in agreement with previous in vitro studies in cell lines regarding the role of MDM2/p53 lymphoid tissue, suggesting a possible role for MDM2 deregulation in lymphomagenesis.


Assuntos
Linfócitos/metabolismo , Linfoma/metabolismo , Proteínas Nucleares , Tonsila Palatina/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Western Blotting , Citometria de Fluxo , Expressão Gênica , Doença de Hodgkin/metabolismo , Humanos , Linfoma não Hodgkin/metabolismo , Proteínas Proto-Oncogênicas c-mdm2
14.
Histopathology ; 26(5): 413-22, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7657310

RESUMO

The morphology, phenotype, genotype and clinical behaviour of four cases of mantle cell lymphoma (centrocytic lymphoma) presenting primarily in mucosa (two gastric, one in large bowel and one tonsillar) are reviewed. Their relationship with the broader group of mantle cell and mucosa-associated lymphoid tissue (MALT) lymphomas is also discussed. All four tumours showed a monomorphic picture of mantle cells (centrocytes) arranged in a diffuse, or vaguely nodular, pattern. Scattered non-neoplastic germinal centres were entrapped within the tumour cells, although there was no follicular colonization. In two cases distinct epithelial infiltration by tumour cells was observed. All four tumours had a CD19, CD20, CD5, IgD, Leu8 immunophenotype, whereas KiM1P and CD10 expression were absent. DRC antibody showed loose aggregates of dendritic cells in three of four cases. Three cases showed PRAD-1/Cyclin D1 overexpression by Northern blot analysis. Although we were not able to detect bcl-1 rearrangement in the major translocation cluster (MTC) breakpoint, the possibility of bcl-1 rearrangement involving other cluster breakpoints cannot be ruled out. The four cases evolved as a disseminated disease, involving either peripheral lymph nodes, spleen or bone marrow. The biological behaviour of mantle cell lymphoma presenting in mucosa appears, irrespective of localization or macroscopic presentation, similar to that of nodal mantle cell lymphoma. Their tendency to dissemination contrasts with MALT lymphomas, which tend to remain localized, and from which mucosa mantle cell lymphoma must be distinguished. The presence of lymphoepithelial lesions does not seem to be a useful differential feature, since occasional epithelial infiltration was seen in two cases. Reactivity with CD5 appears to be especially useful in distinguishing these, since all four cases were clearly positive, in contrast with what is usually found in MALT lymphomas.


Assuntos
Neoplasias Intestinais/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma não Hodgkin/patologia , Neoplasias Gástricas/patologia , Neoplasias Tonsilares/patologia , Idoso , Antígenos de Superfície/análise , Ciclina D1 , Ciclinas/biossíntese , Ciclinas/genética , Feminino , Humanos , Metástase Linfática , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Tonsilares/genética
15.
Blood ; 82(10): 3151-6, 1993 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-8219204

RESUMO

p53 overexpression has been found to be a fairly common feature in high grade lymphomas in the majority of tumoral cells. The results vary from series to series, from 25% to 33% of cases. To assess whether immunohistochemical positivity for p53 correlated with the presence of structural gene abnormalities, DNA from 16 non-Hodgkin's lymphomas with high and low p53 values was amplified and sequenced to determine the existence of point mutations in the highly conserved regions of the p53 gene. In the group of 8 cases containing high levels of protein, 3 cases showed missense point mutations at the codons mapping between exons 5 through 8. Of the 8 cases of tumors containing undetectable or low levels of p53 protein, 1 case presented a nonsense point mutation giving a stop codon. No missense mutations were detected in this group. The finding of p53 mutations in 4 of 16 cases confirms the presence of p53 gene mutations in high grade lymphomas distributed over different histologic groups. These include Burkitt's lymphoma, together with centroblastic, immunoblastic, and large cell lymphoma of mucosa origin. Nevertheless, the absence of mutations in 5 of the 8 cases that overexpressed p53 suggests that the nuclear or cytoplasmic stabilization of p53 protein could also depend on other factors. The absence of detectable levels of p53 protein cannot discount the existence of p53 mutations, as is shown by a case of Burkitt's lymphoma in which a nonsense mutation was detected. The impact of this range of p53 alterations on clinical course and treatment response of the patients deserves to be explored, in an attempt to differentiate the specific consequences of each one.


Assuntos
Genes p53 , Linfoma não Hodgkin/genética , Proteína Supressora de Tumor p53/análise , Sequência de Bases , Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67 , Linfoma não Hodgkin/metabolismo , Dados de Sequência Molecular , Mutação , Proteínas de Neoplasias/análise , Proteínas Nucleares/análise
16.
J Pathol ; 169(4): 405-12, 1993 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8501537

RESUMO

The retinoblastoma susceptibility gene (Rb) has been characterized as a tumour suppressor gene. Rb protein is involved in cell-cycle control, regulating gene transcription. The absence of Rb protein in inherited retinoblastoma has been proved to be the result of inactivation of both Rb alleles through mutation or deletion, according to the general model for suppressor genes. The frequent detection of Rb gene alterations in human tumours (retinoblastoma, osteosarcoma, bladder carcinoma, small-cell lung carcinoma) and the correlation with clinical outcome found in some tumours prompted us to study Rb gene expression in lymphoid tumours in an attempt to determine whether Rb gene expression is related to histological type and degree of aggressivity in human lymphomas. To establish normal levels of Rb protein, its expression was analysed in vitro on cytospin preparations from normal and pokeweed mitogen (PWM) or phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs), using a monoclonal antibody (PMG3-245). Rb protein expression in vivo was quantified using a computer analysis system (CAS) on frozen sections from reactive and neoplastic lymphoid tissue. As a control of tissue preservation, and to compare Rb expression and growth fraction, the tumours and cells were labelled simultaneously with the Ki67 monoclonal antibody. Normal and stimulated lymphocytes showed a gradual increase of Rb protein during progression of the cell cycle, with a peak in the M phase. G0-G1 cells had no detectable levels of Rb protein, suggesting that the Rb gene may act as a 'status quo' cellular growth fraction control mechanism. In reactive lymphoid tissue, Rb protein was mainly expressed in germinal centres (lymph nodes, tonsils) and cortical thymocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Linfoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteína do Retinoblastoma/análise , Anticorpos Monoclonais , Ciclo Celular/fisiologia , Linhagem Celular , Expressão Gênica/fisiologia , Genes Supressores de Tumor/genética , Humanos , Imuno-Histoquímica , Antígeno Ki-67 , Linfócitos/efeitos dos fármacos , Tecido Linfoide/metabolismo , Linfoma/patologia , Linfoma não Hodgkin/metabolismo , Fito-Hemaglutininas , Mitógenos de Phytolacca americana , Proteína do Retinoblastoma/genética
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