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1.
Hematol Oncol ; 33(1): 23-30, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24496723

RESUMO

BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B-cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger-sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B-cell lymphomas, including Richter's syndrome DLBCL, marginal-zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated and common-variable immunodeficiency-associated DLBCL, all known to harbour ASHM-dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV-DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post-transplant lymphoproliferative disorders and 1/2 (50%) common-variable immunodeficiency-associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart.


Assuntos
Linfoma de Células B/genética , Linfoma Folicular/genética , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Análise Mutacional de DNA , Frequência do Gene , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma de Células B/metabolismo , Linfoma Folicular/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Translocação Genética
2.
Blood ; 117(23): 6227-36, 2011 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-21460242

RESUMO

Gastric marginal zone B-cell lymphoma of MALT type (MALT lymphoma) arises in the context of chronic inflammation induced by the bacterial pathogen Helicobacter pylori. Although generally considered an indolent disease, MALT lymphoma may transform to gastric diffuse large B-cell lymphoma (gDLBCL) through mechanisms that remain poorly understood. By comparing microRNA expression profiles of gastric MALT lymphoma and gDLBCL, we have identified a signature of 27 deregulated microRNAs(miRNAs) that share the characteristic of being transcriptionally repressed by Myc. Myc overexpression was consequently detected in 80% of gDLBCL but only 20% of MALT lymphomas spotted on a tissue microarray. A highly similar signature of Myc-repressed miRNAs was further detected in nodal DLBCL. Small interfering RNA-mediated knock-down of Myc blocked proliferation of DLBCL cell lines. Of the Myc-repressed miRNAs down-regulated in malignant lymphoma, miR-34a showed the strongest antiproliferative properties when overexpressed in DLBCL cells. We could further attribute miR-34a's tumor-suppressive effects to deregulation of its target FoxP1. FoxP1 overexpression was detected in gDLBCL but not in gastric MALT lymphoma; FoxP1 knock-down efficiently blocked DLBCL proliferation. In conclusion, our results elucidate a novel Myc- and FoxP1-dependent pathway of malignant transformation and suggest miR-34a replacement therapy as a promising strategy in lymphoma treatment.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , MicroRNAs/metabolismo , RNA Neoplásico/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/genética , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Helicobacter pylori , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , Proteínas Repressoras/genética , Neoplasias Gástricas/genética
3.
Blood ; 113(11): 2488-97, 2009 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-19075189

RESUMO

Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.


Assuntos
Transformação Celular Neoplásica/genética , Epigênese Genética/fisiologia , Perfilação da Expressão Gênica , Genômica/métodos , Linfoma de Células B/genética , Análise de Sequência com Séries de Oligonucleotídeos , Transformação Celular Neoplásica/patologia , Metilação de DNA/fisiologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/fisiologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/fisiologia , Humanos , Linfoma de Células B/patologia , Masculino , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Transcrição Gênica/fisiologia , Células Tumorais Cultivadas
4.
N Engl J Med ; 354(23): 2419-30, 2006 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-16760442

RESUMO

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. METHODS: We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. RESULTS: We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. CONCLUSIONS: Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.


Assuntos
Linfoma de Burkitt/genética , Perfilação da Expressão Gênica , Expressão Gênica , Linfoma de Células B/genética , Algoritmos , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , DNA de Neoplasias/análise , Diagnóstico Diferencial , Feminino , Seguimentos , Genes de Imunoglobulinas , Genes bcl-2 , Genes myc , Humanos , Linfoma de Células B/classificação , Linfoma de Células B/diagnóstico , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/genética , Prognóstico , RNA Neoplásico/análise , Taxa de Sobrevida , Transcrição Gênica , Translocação Genética
5.
Haematologica ; 94(11): 1569-80, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19880780

RESUMO

BACKGROUND: Research on prognostically relevant immunohistochemical markers in diffuse large B-cell lymphomas has mostly been performed on retrospectively collected clinical data. This is also true for immunohistochemical classifiers that are thought to reflect the cell-of-origin subclassification of gene expression studies. In order to obtain deeper insight into the heterogeneous prognosis of diffuse large B-cell lymphomas and to validate a previously published immunohistochemical classifier, we analyzed data from a large set of cases from prospective clinical trials with long-term follow-up. DESIGN AND METHODS: We performed morphological and extensive immunohistochemical analyses in 414 cases of diffuse large B-cell lymphoma from two prospective randomized clinical trials (NHL-B1/B2, Germany). Classification into germinal center and non-germinal center subtypes of B-cell lymphoma was based on the expression pattern of CD10, BCL6, and IRF4. Multivariate analyses were performed adjusting for the factors in the International Prognostic Index. RESULTS: Analyzing 20 different epitopes on tissue microarrays, expression of HLA-DR, presence of CD23(+) follicular dendritic cell meshworks, and monotypic light chain expression emerged as International Prognostic Index-independent markers of superior overall survival. Immunoblastic morphology was found to be related to poor event-free survival. The non-germinal center subtype, according to the three-epitope classifier (CD10, BCL6, and IRF4) did not have prognostic relevance when adjusted for International Prognostic Index factors (relative risk=1.2, p=0.328 for overall survival; and relative risk=1.1, p=0.644 for event-free survival). CONCLUSIONS: The previously reported International Prognostic Index-independent prognostic value of stratification into germinal center/non-germinal center B-cell lymphoma using the expression pattern of CD10, BCL6, and IRF4 was not reproducible in our series. However, other markers and the morphological subtype appear to be of prognostic value.


Assuntos
Antígenos HLA-DR/análise , Linfoma Difuso de Grandes Células B/diagnóstico , Adolescente , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Adulto Jovem
6.
Genome Med ; 11(1): 27, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039827

RESUMO

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Transcriptoma , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Aprendizado de Máquina
7.
Haematologica ; 93(5): 688-96, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18367485

RESUMO

BACKGROUND: The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma. DESIGN AND METHODS: We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling. RESULTS: A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (p<0.001). Cases with 18q21/MALT1 gain more frequently showed an activated B-cell-like (ABC) gene expression signature (65%) than a germinal center B-cell-like (GCB) one (23%) (p<0.001). Ninety-eight genes including MALT1, BCL2, and some selected nuclear factor-kappaB target genes were differentially expressed between the two genetic groups of diffuse large B-cell lymphoma. By global testing of each chromosome, we identified 33 genes, all located on chromosome 18q, which were differentially expressed between the two genetic groups independently of the ABC/GCB status. In multivariate analysis, the 18q21/MALT1 status represented an independent negative prognostic factor for overall survival (p=0.03). CONCLUSIONS: In diffuse large B-cell lymphoma, gain of 18q21 including MALT1 is significantly associated with differential expression of genes located on 18q, the ABC gene expression subtype, increased BCL2 gene and protein expression and might indicate an unfavorable prognosis.


Assuntos
Linfócitos B/citologia , Caspases/genética , Cromossomos Humanos Par 18 , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Idoso , Feminino , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Hibridização de Ácido Nucleico , Prognóstico , Transcrição Gênica
8.
Onkologie ; 31(10): 514-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18854650

RESUMO

BACKGROUND: Mesenteric alterations are associated with non-Hodgkin's lymphoma (NHL), but the frequency and prognostic value of mesenteric alterations are unknown in patients with NHL. PATIENTS AND METHODS: We retrospectively screened 120 patients that were treated for NHL between January 1996 and December 2001 for the presence of mesenteric alterations, defined on computed tomography (CT) scans as nodular or diffuse infiltration of the abdominal mesentery with increased density of mesenteric fat. RESULTS: 21 patients (17.5%) had radiological findings of mesenteric alterations at the time of the initial NHL diagnosis. Mesenteric alterations were significantly associated with mesenteric lymphadenopathy (p = 0.01). In about 50% of the patients, mesenteric alterations could not be explained by direct mesenteric tumour invasion or overt lymphatic obstruction. Patients with initial findings of mesenteric alterations tended to have a better 4-year survival as compared to patients without such findings (79 vs. 43%, p = 0.11). The International Prognostic Index (IPI) score was the only independent predictor of survival in the multivariate analysis. CONCLUSION: This retrospective screening study found a moderate prevalence of mesenteric alterations in patients with various subtypes of NHL. The diagnostic and prognostic value of mesenteric alterations should be further assessed in prospective studies.


Assuntos
Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/mortalidade , Mesentério/diagnóstico por imagem , Paniculite Peritoneal/diagnóstico por imagem , Paniculite Peritoneal/mortalidade , Medição de Risco/métodos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Suíça/epidemiologia , Adulto Jovem
9.
Hum Pathol ; 36(1): 91-100, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15712187

RESUMO

Cytogenetic and molecular analyses are essential disease-monitoring parameters in chronic myelogenous leukemia (CML) treated with imatinib. However, a bone marrow morphologic response has not been defined. We reviewed bone marrow histology and cytology of 39 imatinib-treated patients with CML over 49 weeks and introduced a morphologic response score. A significant positive correlation with a complete cytogenetic response was shown for absence of dry tap (P = .04) and abnormal megakaryocytes (P < 0.001), normalization of cellularity (P = .001) and reduction of fibrosis (P = .01), myelopoiesis:erythropoiesis index (P = .001), blast (P = .001) and basophil count (P < 0.001). The morphologic score integrating these parameters showed an early and late correlation with cytogenetic response. In conclusion, morphologic criteria for complete cytogenetic response in patients with CML treated with imatinib can be defined. Persistent high-level morphologic abnormalities herald early on a high likelihood to fail treatment and call for more intense or alternative therapy.


Assuntos
Antineoplásicos/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Células da Medula Óssea/citologia , Ensaios Clínicos como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
10.
Swiss Med Wkly ; 135(9-10): 151-9, 2005 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-15832234

RESUMO

The diagnostic impact of bone marrow cytology in combination with flow cytometry analysis of aspirate smears and bone marrow histology together with immunohistochemical examination of trephine biopsies was compared in 141 routine cases. Diagnoses achieved by the two methods were concordant in 80.5% of cases. In discordant cases, clinical follow-up data of at least one year confirmed the correctness of cytological and histological diagnoses. For infiltration by malignant disease, both methods were concordant in 86.5% of samples and correlated well for the degree of infiltration (r = 0.64, p <0.001). Overall, regression analysis showed a good correlation for cellularity (r = 0.67) lymphopoiesis (r = 0.75), granulopoiesis (r = 0.73) and megakaryopoiesis (r = 0.65) while erythropoiesis displayed a lower degree of correlation (r = 0.43, all p <0.001). Regression analysis on all immunological data obtained by flow cytometry (FC) and immunohistochemistry (IHC) showed a good overall linear correlation (r = 0.67, p <0.001), but significant differences were found for a few phenotypic markers. Furthermore, the correlation was found to be dependent on IgG subclasses and the fluorochromes used for FC. Thus, analyses with IgG2 antibodies and phycoerythrin (PE) as fluorochrome showed significantly more expression than IHC. In conclusion, cytology and histology, both in association with the respective immunophenotyping, are of equal value in bone marrow diagnostics and should be used in combination. However, in some specific settings, one of the two procedures might be preferable.


Assuntos
Doenças da Medula Óssea/diagnóstico , Medula Óssea/patologia , Anticorpos/análise , Biomarcadores/análise , Biópsia , Exame de Medula Óssea/métodos , Citometria de Fluxo , Humanos , Imunoglobulina G/imunologia , Imuno-Histoquímica , Imunofenotipagem , Ficoeritrina , Análise de Regressão , Coloração e Rotulagem
11.
Swiss Med Wkly ; 132(43-44): 607-17, 2002 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-12587044

RESUMO

The principles of the new WHO classification of haematopoietic and lymphoid tumours are based on those defined in the Revised European American classification of Lymphoid neoplasms (REAL), published by the International Lymphoma Study Group (ILSG) in 1994. Thus, the new WHO classification may be considered an updated version of the REAL classification rather than of the old WHO classification published in 1976. Disease entities are defined on the basis of morphological, phenotypic, genotypic, and clinical data. The relative impact of these characteristics varies among different diseases and there is "no gold standard". Thus, the strict hierarchy among diagnostic criteria, headed by morphology and followed by immunohistochemistry and genetics, has been discontinued. The WHO classification not only encompasses lymphoid tumours but extends to myeloid, mast cell and histiocytic/dendritic cell malignancies. Neoplasms are primarily stratified according to their tumour cell lineage. For each neoplasm a cell of origin is postulated. The classification of lymphoid malignancies recognises three major categories, B-cell neoplasms, T-/NK-cell neoplasms, and Hodgkin lymphomas. B-cell and T-cell lymphomas are further divided into precursor neoplasms and mature neoplasms, the latter being subdivided according to their clinical manifestation into disseminated/leukaemic, extranodal and nodal malignancies. In contrast to previous classifications, the neoplasms are grouped neither according to their histological grade (Kiel classification) nor according to their clinical aggressiveness (International Working Formulation). However, the histological grade is considered a prognostic factor which enters into the description of each disease entity. Hodgkin's disease, now more appropriately termed Hodgkin lymphoma, comprises nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphomas of nodular sclerosis, mixed cellularity, lymphocyte-depleted and lymphocyte-rich subtype. For practical purposes this minireview disregards the description of myeloid, macrophage/histiocytic, dendritic cell and mast cell disorders. Furthermore, the present paper is restricted to those lymphoid tumours that are not already identically described in the REAL classification, in order to focus on what is really new in the WHO classification.


Assuntos
Classificação Internacional de Doenças/classificação , Classificação Internacional de Doenças/normas , Linfoma/classificação , Organização Mundial da Saúde , Europa (Continente) , Humanos , Estados Unidos
12.
Cancer Res ; 71(10): 3616-24, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21454413

RESUMO

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) develops in the chronically inflamed mucosa of patients infected with the bacterial pathogen Helicobacter pylori. Here we use patient material, primary gastric lymphoma cell cultures, and a preclinical model of the disease to examine the role of microRNA (miRNA)-mediated posttranscriptional regulation--focusing in particular on miR-203 and its target ABL1--in gastric MALT lymphomagenesis. Microarray-based miRNA expression profiling revealed a strong downregulation of the putative tumor suppressor miRNA miR-203 in human MALT lymphoma samples, which resulted from extensive promoter hypermethylation of the miR-203 locus and coincided with the dysregulation of the miR-203 target ABL1 in lymphoma biopsies compared with matched adjacent normal material from the same patients. Treatment of lymphoma B cells with demethylating agents led to increased miR-203 expression and the concomitant downregulation of ABL1, confirming the epigenetic regulation of this miRNA. Ectopic reexpression of miR-203 by transfection of a human lymphoma cell line or lentiviral transduction of explanted primary MALT lymphoma cells was sufficient to prevent tumor cell proliferation in vitro. Similarly, the treatment of primary MALT lymphoma cells with the ABL inhibitors imatinib and dasatinib prevented tumor cell growth. Finally, we show that the treatment of tumor-bearing mice with imatinib induces MALT lymphoma regression in a preclinical model of the disease, implicating ABL1 in MALT lymphoma progression. In summary, our results show that the transformation from gastritis to MALT lymphoma is epigenetically regulated by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy.


Assuntos
Epigênese Genética , Inativação Gênica , Helicobacter pylori/metabolismo , Linfoma de Zona Marginal Tipo Células B/genética , MicroRNAs/metabolismo , Proteínas Oncogênicas v-abl/genética , Neoplasias Gástricas/genética , Animais , Benzamidas , Biópsia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Mesilato de Imatinib , Linfoma de Zona Marginal Tipo Células B/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Oncogênicas v-abl/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Neoplasias Gástricas/microbiologia
13.
Pediatr Blood Cancer ; 49(7): 1039-46, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16572408
14.
Br J Haematol ; 134(3): 294-301, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16848772

RESUMO

The quick diagnosis of Burkitt lymphoma (BL) and its clear-cut differentiation from diffuse large B-cell lymphoma (DLBCL) is of great clinical importance because treatment strategies for these two disease entities differ markedly. As these two lymphomas are difficult to distinguish using the current World Health Organization classification, we studied 39 cases of highly proliferative peripheral blastic B-cell lymphoma (HPBCL) to establish a practical differential-diagnostic algorithm. Characteristics set for BL were a typical morphology, a mature B-cell phenotype of CD10+, Bcl-6+ and Bcl-2- tumour cells, a proliferation rate of >95%, and the presence of C-MYC rearrangements in the absence of t(14;18)(q32;q21). Altogether, these characteristics were found in only five of 39 cases, whereas the majority of tumours revealed mosaic features. We then followed a pragmatic stepwise approach for a classification algorithm that included the assessment of C-MYC status to stratify HPBCL into four predefined diagnostic categories (DC), namely DC I (5/39, 12.8%): 'classical BL', DC II (11/39, 28.2%): 'atypical BL', DC III (9/39, 23.1%): 'C-MYC+ DLBCL' and DC IV (14/39, 35.9%): 'C-MYC- HPBCL'. This proposal may serve as a robust and objective operational basis for therapeutic decisions for HPBCL within 1 week and is applicable to be evaluated for its prognostic relevance in clinical trials with uniformly treated patients.


Assuntos
Linfoma de Burkitt/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Linfoma de Burkitt/classificação , Linfoma de Burkitt/mortalidade , Diagnóstico Diferencial , Feminino , Rearranjo Gênico , Genes myc , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Neprilisina/análise , Taxa de Sobrevida , Translocação Genética
15.
J Pathol ; 206(3): 320-7, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15887292

RESUMO

Mantle cell lymphoma (MCL) is associated with a very unfavourable clinical course. This is particularly true for mantle cell lymphoma of the blastoid subtype (MCL-b). In order to define prognostic factors, we analysed the impact of immunoglobulin heavy chain variable (IgV H) gene somatic hypermutations on clinical outcome in a series of 21 cases of morphologically, phenotypically, and genotypically well-characterized MCL-b. Testing and estimation were performed using log-rank statistics and displayed on Kaplan-Meier graphs. Thirteen of 21 cases of MCL-b revealed a homology rate of > or = 99% compared to IgV H germ-line sequences in the databases and were scored as non-mutated. Eight of 21 cases (38%) of MCL-b were mutated. In MCL-b the mutation frequency was usually low and the mutation pattern was only rarely antigen-selected, in contrast to a control group of 11 cases with morphologically almost identical, but phenotypically and genotypically clearly distinguishable, diffuse large B cell lymphoma, derived, most likely, from germinal centre B cells. In our series of 21 MCL-b, positive IgV H mutational status, irrespective of varying homology thresholds, had no statistically significant prognostic impact on event-free or overall survival. However, mutated MCL-b tended to present more frequently at an earlier stage and without bone marrow involvement and to show lower rates of relapse and death, resulting in a more favourable clinical outcome.


Assuntos
Genes de Imunoglobulinas/genética , Linfoma de Célula do Manto/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Imunofenotipagem/métodos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Análise de Sequência de DNA/métodos , Análise de Sobrevida
16.
Br J Haematol ; 124(3): 289-98, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14717775

RESUMO

Mantle cell lymphoma (MCL) shares immunophenotypic and karyotypic features with chronic lymphocytic leukaemia. The latter comprises two distinct entities with prognosis dependent upon immunoglobulin heavy chain (IgH) gene mutational status and the presence of 11q deletion. We evaluated the relevance of IgH gene mutational status, IgV gene family usage and presence of 11q deletion in a series of 42 histologically reviewed classical MCL cases to determine the prognostic impact. VH3 was the most common VH family, with VH3-21 being the most frequent individual VH gene. Approximately 30% of the cases had a IgH somatic mutation rate higher than 2%, but was only higher than 4% in <10% of cases. Half of the cases had deletion of chromosome 11q21-telomere (11q21->ter), with two minimal deleted regions, at 11q22.2 and 11q23.2. There was no association between 11q loss and IgH gene somatic mutation rate; the use of VH3-21 gene could be associated with a better prognosis.


Assuntos
Cromossomos Humanos Par 11 , Deleção de Genes , Genes de Imunoglobulinas , Linfoma de Célula do Manto/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico
17.
Blood ; 103(12): 4416-23, 2004 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-14976046

RESUMO

The potential benefits of extended rituximab treatment have been investigated in a randomized trial comparing the standard schedule with prolonged treatment in 202 patients with newly diagnosed or refractory/relapsed follicular lymphoma (FL). All patients received standard treatment (rituximab 375 mg/m(2) weekly x 4). In 185 evaluable patients, the overall response rate was 67% in chemotherapy-naive patients and 46% in pretreated cases (P <.01). Patients responding or with stable disease at week 12 (n = 151) were randomized to no further treatment or prolonged rituximab administration (375 mg/m(2) every 2 months for 4 times). At a median follow-up of 35 months, the median event-free survival (EFS) was 12 months in the no further treatment versus 23 months in the prolonged treatment arm (P =.02), the difference being particularly notable in chemotherapy-naive patients (19 vs 36 months; P =.009) and in patients responding to induction treatment (16 vs 36 months; P =.004). The number of t(14;18)-positive cells in peripheral blood (P =.0035) and in bone marrow (P =.0052) at baseline was predictive for clinical response. Circulating normal B lymphocytes and immunoglobulin M (IgM) plasma levels decreased for a significantly longer time after prolonged treatment, but the incidence of adverse events was not increased. In patients with FL, the administration of 4 additional doses of rituximab at 8-week intervals significantly improves the EFS.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Murinos , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Primers do DNA , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Folicular/fisiopatologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Rituximab , Fatores de Tempo
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