RESUMO
Methylation of CpG islands in promoter gene regions is frequently observed in lymphomas. DNA methylation is established by DNA methyltransferases (DNMTs). DNMT1 maintains methylation patterns, while DNMT3A and DNMT3B are critical for de novo DNA methylation. Little is known about the expression of DNMTs in lymphomas. DNMT3A and 3B genes can be regulated post-transcriptionally by miR-29 family. Here, we demonstrated for the first time the overexpression of DNMT1 and DNMT3B in Burkitt lymphoma (BL) tumor samples (69% and 86%, respectively). Specifically, the treatment of two BL cell lines with the DNMT inhibitor 5-aza-dC decreased DNMT1 and DNMT3B protein levels and inhibited cell growth. Additionally, miR-29a, miR-29b and miR-29c levels were significantly decreased in the BL tumor samples. Besides, the ectopic expression of miR-29a, miR-29b and miR-29c reduced the DNMT3B expression and miR-29a and miR-29b lead to increase of p16(INK4a) mRNA expression. Altogether, our data suggest that deregulation of DNMT1, DNMT3B and miR29 may be involved in BL pathogenesis.
Assuntos
Linfoma de Burkitt/genética , DNA (Citosina-5-)-Metiltransferases/biossíntese , MicroRNAs/biossíntese , Adolescente , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/farmacologia , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , DNA Metiltransferase 3BRESUMO
CDKN2A is a tumor suppressor gene critical in the cell cycle regulation. Little is known regarding the role of CDKN2A methylation in the pathogenesis of Burkitt lymphoma (BL). CDKN2A methylation was investigated using pyrosequencing in 51 tumor samples. p16(INK4a) mRNA and protein levels were measured using real-time PCR and immunohistochemistry, respectively. CDKN2A methylation was detectable in 72% cases. Nuclear expression of p16(INK4a) was not detected in 41% cases. There was an association between methylation and absence of CDKN2A mRNA (P=0.003). In conclusion, CDKN2A methylation occurs at a high frequency suggesting a role in BL pathogenesis and potential therapeutic implications.
Assuntos
Linfoma de Burkitt/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Metilação de DNA , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Adolescente , Linfoma de Burkitt/genética , Linhagem Celular Tumoral , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , RNA Mensageiro/genética , RNA Neoplásico/genéticaRESUMO
PURPOSE: This study determined the frequency of clinical features, reactivations, sequelae, mortality, and overall survival (OS) and compared paediatric with adult Langerhans cell histiocytosis (LCH) patients. MATERIALS AND METHODS: Ninety patients (60 paediatric and 30 adults) with LCH treated during 28 years were analysed retrospectively. RESULTS: Craniofacial lesion was the most frequent lesion at LCH presentation in children and adults. However, some differences were found. Orbital lesions were more frequent in paediatric than adult patients (P = 0.001). There was a tendency for mandible lesions to be more common in adults than the paediatric group (P = 0.0710). Mucocutaneous lesions were observed in a higher proportion in adults compared to paediatric patients (P = 0.0395). Reactivation episodes (36.8 versus 62.5%) and deaths (10.7 versus 24.0%) occurred in lower proportions in paediatric than adult patients, respectively. The probability of OS in 10 years for both groups was similar (P = 0.137). CONCLUSION: The OS was similar in both groups despite clinical differences between paediatric and adult patients, and higher reactivation and death rates in adults.
