RESUMO
Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.
Assuntos
Linfoma Folicular/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Complexos Multiproteicos/genética , Mutação , Serina-Treonina Quinases TOR/genética , Sequência de Aminoácidos , Animais , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Dados de Sequência Molecular , Proteínas Monoméricas de Ligação ao GTP/química , Complexos Multiproteicos/química , Homologia de Sequência de Aminoácidos , Serina-Treonina Quinases TOR/químicaRESUMO
The purpose of this work was to modernize recommendations for evaluation, staging, and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to revised criteria for staging and of the International Working Group Guidelines of 2007 for response. As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)computed tomography (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modification of the Ann Arbor descriptive terminology will be used for anatomic distribution of disease extent, but the suffixes A or B for symptoms will only be included for HL. A bone marrow biopsy is no longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. However, regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky) or advanced (stage III or IV) disease, with stage II bulky disease considered as limited or advanced disease based on histology and a number of prognostic factors. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale. The product of the perpendicular diameters of a single node can be used to identify progressive disease. Routine surveillance scans are discouraged. These recommendations should improve evaluation of patients with lymphoma and enhance the ability to compare outcomes of clinical trials.
Assuntos
Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/terapia , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/terapia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Neoplasias da Medula Óssea/diagnóstico por imagem , Neoplasias da Medula Óssea/secundário , Fluordesoxiglucose F18 , Doença de Hodgkin/patologia , Humanos , Cooperação Internacional , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Linfoma não Hodgkin/patologia , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons/métodos , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/história , Biomarcadores Tumorais/análise , Bleomicina/administração & dosagem , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Europa (Continente)/epidemiologia , História do Século XX , Doença de Hodgkin/história , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Mecloretamina/administração & dosagem , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vimblastina/administração & dosagem , Vincristina/administração & dosagemRESUMO
Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.
Assuntos
Transformação Celular Neoplásica/genética , Progressão da Doença , Genômica/métodos , Linfoma Folicular/genética , Linfoma Folicular/fisiopatologia , Sequência de Bases , Proteína de Ligação a CREB/genética , Análise por Conglomerados , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Anotação de Sequência Molecular , Dados de Sequência Molecular , Mutagênese , Mutação/genética , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Filogenia , Complexo Repressor Polycomb 2/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Transativadores/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfaRESUMO
Problems of sexual function and fertility in long-term survivors (≥5 years) of haematological malignancy are often neglected in clinic. Our centre carried out a questionnaire study in this population addressing patient-perceived fertility and sexual function. 718 patients responded (56% of those invited; 39% Hodgkin, 45% non-Hodgkin lymphoma, 16% acute leukaemia). Respondent women were more likely to remain childless than a normal control population. Self-reported infertility was more likely in men than women [odds ratio (OR) 1·77, P = 0·001]. Myeloablative therapy increased the likelihood of childlessness (OR 2·48, P = 0·004). Few attended fertility support services (12%). 24% of men banked sperm and 29% of these used the sample, of which 46% resulted in successful pregnancy. Fertility clinic attendance and sperm storage was more likely post-1990 (OR 4·05, P < 0·001; OR 5·05, P < 0·001 respectively). Reporting a negative impact of cancer on sexual function was more common in women than men (OR 2·20, P < 0·001), and increased with current age and age at diagnosis (by 3-4% per year, P ≤ 0·001) but decreased with longer follow-up (by 2%/year, P = 0·005). Patients on anti-depressants and those reporting cancer-related body change/appearance concerns more frequently reported a negative impact (P < 0·04 and P < 0·03 respectively). These self-reported outcomes confirm literature findings, suggest improvement over time, but highlight a need for involvement of support services.
Assuntos
Neoplasias Hematológicas/fisiopatologia , Infertilidade/etiologia , Disfunções Sexuais Fisiológicas/etiologia , Adolescente , Adulto , Feminino , Humanos , Infertilidade/fisiopatologia , Masculino , Gravidez , Qualidade de Vida , Autorrelato , Disfunções Sexuais Fisiológicas/fisiopatologia , Inquéritos e Questionários , Sobreviventes , Resultado do Tratamento , Adulto JovemRESUMO
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
Assuntos
Biomarcadores Tumorais/genética , Linfoma Folicular/genética , Mutação , Complexo Repressor Polycomb 2/genética , Proteína de Ligação a CREB/genética , Estudos de Coortes , Análise Mutacional de DNA , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste , Perfilação da Expressão Gênica , Frequência do Gene , Humanos , Estimativa de Kaplan-Meier , Linfoma Folicular/patologia , Fatores de Transcrição MEF2/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Fatores de TempoRESUMO
PURPOSE: The immune microenvironment is key to the pathophysiology of classical Hodgkin lymphoma (CHL). Twenty percent of patients experience failure of their initial treatment, and others receive excessively toxic treatment. Prognostic scores and biomarkers have yet to influence outcomes significantly. Previous biomarker studies have been limited by the extent of tissue analyzed, statistical inconsistencies, and failure to validate findings. We aimed to overcome these limitations by validating recently identified microenvironment biomarkers (CD68, FOXP3, and CD20) in a new patient cohort with a greater extent of tissue and by using rigorous statistical methodology. PATIENTS AND METHODS: Diagnostic tissue from 122 patients with CHL was microarrayed and stained, and positive cells were counted across 10 to 20 high-powered fields per patient by using an automated system. Two statistical analyses were performed: a categorical analysis with test/validation set-defined cut points and Kaplan-Meier estimated outcome measures of 5-year overall survival (OS), disease-specific survival (DSS), and freedom from first-line treatment failure (FFTF) and an independent multivariate analysis of absolute uncategorized counts. RESULTS: Increased CD20 expression confers superior OS. Increased FOXP3 expression confers superior OS, and increased CD68 confers inferior FFTF and OS. FOXP3 varies independently of CD68 expression and retains significance when analyzed as a continuous variable in multivariate analysis. A simple score combining FOXP3 and CD68 discriminates three groups: FFTF 93%, 62%, and 47% (P < .001), DSS 93%, 82%, and 63% (P = .03), and OS 93%, 82%, and 59% (P = .002). CONCLUSION: We have independently validated CD68, FOXP3, and CD20 as prognostic biomarkers in CHL, and we demonstrate, to the best of our knowledge for the first time, that combining FOXP3 and CD68 may further improve prognostic stratification.
Assuntos
Antígenos CD20/biossíntese , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Fatores de Transcrição Forkhead/biossíntese , Doença de Hodgkin/metabolismo , Biomarcadores Tumorais/biossíntese , Feminino , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Microambiente TumoralRESUMO
Defining the role of high-dose therapy with autologous stem cell rescue in the therapeutic algorithm of follicular lymphoma remains a major challenge. In contrast to the acknowledged poor outcome associated with cyclophosphamide/total body irradiation conditioning in heavily pretreated patients, the prognostic impact of the number of previous therapy lines in patients treated with the chemotherapy-only containing regimen, BEAM, is unknown. From 1997 to 2008 80 patients (41 males, 39 females; median age, 51 years; range, 31-67) received high-dose therapy with autologous stem cell rescue with BEAM for relapsed follicular lymphoma at our center. Overall survival and time-to-progression were analyzed according to the number of prior treatment lines. The median number of previous treatment lines was three, with 61% of the patients having received more than three lines (including rituximab in 47%). After a median follow-up of 76 months (range, 14-160), three patients developed secondary myelodysplastic syndrome. The 5-year overall survival rate was 71% and 5-year time-to-progression was 44%. There were no differences in time-to-progression or overall survival according to the number of previous treatment lines or episodes of disease. In conclusion, high-dose therapy with autologous stem cell rescue with BEAM appears to be equally effective in second or third remission of follicular lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Folicular/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Hibridização In Situ , Estimativa de Kaplan-Meier , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/genética , Recidiva Local de Neoplasia , Prognóstico , Indução de Remissão , Fatores de Tempo , Transplante Autólogo , Resultado do TratamentoRESUMO
PURPOSE: To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. PATIENTS AND METHODS: Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. RESULTS: Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age ≥ 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving ≥ 40 Gy mantle radiotherapy at young ages was 48%. CONCLUSION: This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages.
Assuntos
Neoplasias da Mama/etiologia , Doença de Hodgkin/radioterapia , Neoplasias Induzidas por Radiação/etiologia , Adolescente , Adulto , Fatores Etários , Estudos de Coortes , Diafragma/efeitos da radiação , Inglaterra , Humanos , Dosagem Radioterapêutica , Risco , País de GalesRESUMO
The relative merits of reduced-intensity allogeneic stem cell transplantation (RISCT) for high-risk indolent lymphoid malignancies are emerging, although the preferred conditioning regimen to manage the risks of graft-versus-host disease (GVHD) is not clearly defined. Here we report the outcome of 73 patients with lymphoid malignancies who received RISCT with a fludarabine/cyclophosphosphamide conditioning regimen and a median follow-up of 3 years. Median age was 54 years. Forty-eight per cent of patients had previously undergone autologous stem cell transplantation with a median of three prior therapies. Non-relapse mortality at 3 years was 19% but only 5% for patients with multiple myeloma (MM). Three-year overall survival and current progression-free survival was 67% and 63% respectively. Grade 2-4 acute GVHD occurred in 14% of patients while 49% had chronic GVHD requiring systemic immunosuppression. The preparatory regimen in this study has the advantage of reduced acute GVHD and low mortality, notably in patients with MM. In addition, this strategy provides long-term disease control in a significant proportion of patients with particular benefit in those with high-risk follicular lymphoma.
Assuntos
Ciclofosfamida/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos/terapia , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Linfócitos T/imunologia , Transplante Homólogo , Vidarabina/administração & dosagemRESUMO
An intention-to-treat (ITT) analysis was performed in 103 unselected patients with relapsed/refractory classical Hodgkin lymphoma (CHL) comparing early relapse (<12 months) or failure of first-line therapy (ER/FTF) with late relapses (LR). Seventy one percentage proceeded to high-dose therapy/autologous stem cell rescue (HDT/ASCR) following salvage treatment. By ITT, 5-year overall survival (OS) was 50% for ER/FTF compared to 73% for LR patients (P = 0·012). However OS was equivalent for both groups if salvage treatment response was adequate to proceed to HDT/ASCR. ER/FTF patients remain a high-risk group largely due to a failure of salvage therapy: a point at which novel interventions could impact survival.
Assuntos
Antraciclinas/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/mortalidade , Doença de Hodgkin/prevenção & controle , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Fatores de Tempo , Transplante AutólogoRESUMO
PURPOSE: We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge. PATIENTS AND METHODS: We followed 5,798 patients with HL treated with chemotherapy in Britain from 1963 to 2001--of whom 3,432 also received radiotherapy--to assess second primary malignancy risks compared with general population-based expectations. RESULTS: Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% CI, 1.7 to 2.4) but was much lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia, each contributing approximately equal absolute excess risk. After combined modalities, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. Risk was raised after each common chemotherapy regimen except, based on limited numbers and follow-up, adriamycin, bleomycin, vinblastine, and dacarbazine. The age and time-course relations of lung cancer differed between chemotherapy alone and combined modalities. CONCLUSION: Although chemotherapy alone leads to raised risk of second malignancy, this risk is lower and affects fewer anatomic sites than that after combined modalities, and it is slight if at all after 15 years follow-up. The mechanism of lung cancer etiology may differ between chemotherapy and radiotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucemia/diagnóstico , Leucemia/epidemiologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/epidemiologia , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologia , Adulto JovemRESUMO
Dysregulation of the Wnt/ß-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the overexpression of ß-catenin is an independent adverse prognostic factor. ß-catenin was found upregulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared with normal bone marrow CD34(+) cells. The knockdown of ß-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates all-trans retinoic acid-induced differentiation and impairs the proliferation of HL60 leukemic cell line. Using in vivo quantitative tracking of these cells, we observed a reduced engraftment potential after xenotransplantation when ß-catenin was silenced. However, when studying primary AML cells, despite effective downregulation of ß-catenin we did not observe any impairment of their in vitro long-term maintenance on MS-5 stroma nor of their engraftment potential in vivo. Altogether, these results show that despite a frequent ß-catenin upregulation in AML, leukemia-initiating cells might not be 'addicted' to this pathway and thus targeted therapy against ß-catenin might not be successful in all patients.
Assuntos
Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , beta Catenina/metabolismo , Adulto , Idoso , Animais , Apoptose , Western Blotting , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Transplante Heterólogo , Células Tumorais Cultivadas , beta Catenina/antagonistas & inibidores , beta Catenina/genéticaRESUMO
Inherited risk determinants for follicular lymphoma (FL) have recently been described in the immune gene-rich human leukocyte antigen region on chromosome 6p. The known importance of host immune response to FL survival led us to evaluate these germline factors in FL outcome. We confirm the association of single nucleotide polymorphisms rs10484561 (P = 3.5 × 10â»9) and rs6457327 (P = .008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL transformation independently of clinical variables, including the Follicular Lymphoma International Prognostic Index.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Cromossomos Humanos Par 6/genética , Antígenos HLA/genética , Linfoma Folicular/genética , Linfoma Folicular/patologia , Polimorfismo de Nucleotídeo Único/genética , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Reino UnidoRESUMO
A variety of genetic lesions, including chromosomal translocations, internal tandem duplications, and mutations, have been described in acute myeloid leukemia (AML). Expression profiling has shown that chromosomal translocations, in particular, are associated with distinctive patterns of gene expression. AML exhibiting the translocation t(8;21), which fuses the AML1 and ETO genes, has such a characteristic expression profile. One gene whose expression is highly correlated with the presence of the AML1/ETO fusion is POU4F1, which encodes the POU homeodomain transcription factor BRN3A. Here we show using specific siRNA in t(8;21) cells and overexpression studies in progenitor cells that AML1/ETO promotes expression of POU4F1/BRN3A. This effect requires DNA-binding function of AML1/ETO, and accordingly, AML1/ETO is bound to the POU4F1 locus in t(8;21) cells. Functionally, whereas overexpression of Brn3a in murine hematopoietic progenitor cells induces terminal myeloid differentiation, coexpression of AML1/ETO or AML1/ETO9a blocks this effect. Furthermore, Brn3a reduction by shRNA impairs AML1/ETO-induced immortalization of murine progenitors. In summary, we identify POU4F1/BRN3A as a novel potential upregulated AML1/ETO target gene whose dramatically high expression may cooperate with AML1/ETO in t(8;21) cells.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição Brn-3A/metabolismo , Adulto , Animais , Sequência de Bases , Western Blotting , Diferenciação Celular , Imunoprecipitação da Cromatina , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Ensaio de Desvio de Mobilidade Eletroforética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/fisiologia , Feto , Imunofluorescência , Células-Tronco Hematopoéticas/fisiologia , Humanos , Técnicas Imunoenzimáticas , Leucemia Mieloide Aguda/patologia , Fígado/citologia , Fígado/metabolismo , Luciferases/metabolismo , Camundongos , Dados de Sequência Molecular , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição Brn-3A/antagonistas & inibidores , Fator de Transcrição Brn-3A/genética , Transfecção , Translocação Genética/genéticaRESUMO
Follicular lymphoma has considerable clinical heterogeneity, and there is a need for easily quantifiable prognostic biomarkers. Microvessel density has been shown to be a useful prognostic factor based on numerical assessment of vessel numbers within histologic sections in some studies, but assessment of tumor neovascularization through angiogenic sprouting may be more relevant. We therefore examined the smallest vessels, single-staining structures measuring less than 30 microm(2) in area, seen within histologic sections, and confirmed that they were neovascular angiogenic sprouts using extended focal imaging. Tissue microarrays composing diagnostic biopsies from patients at the extremes of survival of follicular lymphoma were analyzed with respect to numbers of these sprouts. This analysis revealed higher angiogenic activity in the poor prognostic group and demonstrated an association between increased sprouting and elevated numbers of infiltrating CD163(+) macrophages within the immediate microenvironment surrounding the neovascular sprout.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores Tumorais/metabolismo , Linfoma Folicular/patologia , Macrófagos/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Biópsia , Humanos , Macrófagos/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , PrognósticoRESUMO
BACKGROUND: The impact of active surveillance, comprising annual computed tomography scanning and bone marrow biopsies, in the follow-up of patients after high-dose therapy with autologous stem cell rescue for recurrent follicular lymphoma was analyzed. DESIGN AND METHODS: Seventy-one of 99 patients who received high-dose therapy commenced the surveillance program. Response duration, time to next treatment and overall survival were compared according to whether disease progression had been diagnosed on the basis of surveillance investigations or on clinical grounds. RESULTS: After a median follow-up of 16 years, progression was documented by surveillance in 16 patients and clinically in 18, the median response duration being 2.4 and 2.3 years, respectively (P=NS). Ten patients with a relapse detected clinically started treatment immediately, contrasting with one patient whose relapse was detected by surveillance investigations. Five patients with relapses detected by surveillance investigations have not required treatment after a median follow-up of 18 years, whereas all but two patients with a relapse detected clinically have been treated. The median time to next treatment was 7 years for patients with a relapse identified by surveillance investigations and 4 years for those whose relapse was manifested clinically (P=0.03). Overall survival was not significantly different between the two groups. CONCLUSIONS: Surveillance investigations, consisting of annual computed tomography scanning and bone marrow biopsies, have no impact on the management of patients with recurrent follicular lymphoma and do not improve the outcome of these patients.