RESUMO
Diffuse large B cell lymphoma (DLBCL) is traced to a mature B malignance carrying abnormal activation-induced cytidine deaminase (AID) expression. AID activity initially focuses on deamination of cytidine to uracil to generate somatic hypermutation and class-switch recombination of the immunoglobulin (Ig), but recently it has been implicated in DNA demethylation of genes required for B cell development and proliferation in the germinal centre (GC). However, whether AID activity on mutation or demethylation of genes involves oncogenesis of DLBCL has not been well characterized. Our data demonstrate that the proto-oncogene Fanconi anaemia complementation group A (FANCA) is highly expressed in DLBCL patients and cell lines, respectively. AID recruits demethylation enzyme ten eleven translocation family member (TET2) to bind the FANCA promoter. As a result, FANCA is demethylated and its expression increases in DLBCL. On the basis of our findings, we have developed a new therapeutic strategy to significantly inhibit DLBCL cell growth by combination of the proteasome inhibitor bortezomib with AID and TET2 depletion. These findings support a novel mechanism that AID has a crucial role in active demethylation for oncogene activation in DLBCL.
Assuntos
Citidina Desaminase/metabolismo , Desmetilação do DNA , Proteínas de Ligação a DNA/metabolismo , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Antineoplásicos/farmacologia , Linfócitos B/metabolismo , Bortezomib/farmacologia , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Citidina Desaminase/genética , Dioxigenases , Modelos Animais de Doenças , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Regulação da Expressão Gênica/genética , Técnicas de Inativação de Genes , Humanos , Switching de Imunoglobulina/genética , Linfoma Difuso de Grandes Células B/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proto-Oncogene Mas , Hipermutação Somática de Imunoglobulina/genéticaRESUMO
Although military conflicts are common on the African continent, there is a paucity of data regarding bomb-blast injuries in this region and in Kenya in particular. This paper describes the pattern of maxillofacial injuries sustained after the August 1998 bomb blast that occurred in Nairobi, Kenya. A retrospective cross-sectional study was carried out using hospital-based records of 290 bomb-blast survivors admitted at the Kenyatta National Referral and Teaching Hospital in Nairobi. Using a self-designed form to record information about variables such as the sex and age of the survivors and type of location of soft- and hard-tissue injuries, it was found that of the 290 bomb-blast survivors, 78% had sustained one or more maxillofacial injuries. Soft-tissue injuries (cuts, lacerations or bruises) were the most common, constituting 61.3% of all injuries in the maxillofacial region; 27.6% had severe eye injuries, while 1.4% had fractures in the cranio-facial region. This paper concludes that the effective management of bomb-blast injuries as well as those caused by other types of disaster requires a multidisciplinary approach. The high percentage of maxillofacial injuries confirm that maxillofacial surgeons should form an integral part of this multidisciplinary team.