RESUMO
PURPOSE OF REVIEW: Burkitt lymphoma is an important clinical and model disease arising from B cells. Burkitt lymphoma is characterized by translocation of the c-MYC gene to an immunoglobulin enhancer region, resulting in enhanced cell proliferation and rapid tumor progression. The development of deep sequencing has widened the scope of genetic analysis to reveal the role of additional collaborating mutations in Burkitt lymphoma. In this review, we examine the role of additional genetic events that cooperate with MYC in Burkitt lymphoma pathogenesis. RECENT FINDINGS: Next-generation sequencing of Burkitt lymphoma has identified recurrent silencing mutations in ID3, a novel tumor suppressor gene. In addition, mutations in a number of genes including GNA13, TP53, and SMARCA4 occur in Burkitt lymphoma. Copy number status has implicated recurrent aberrations including gains of 1q and 18q and deletion of 19p13. Additionally, microRNA and gene expression profiling has revealed unique transcriptome signatures in Burkitt lymphoma subgroups. SUMMARY: Analysis of genetic alterations in Burkitt lymphoma has yielded a better understanding of the pathogenesis of this disease. These observations could lead to more effective strategies for the diagnosis and treatment of Burkitt lymphoma.
Assuntos
Linfoma de Burkitt/genética , Animais , Linfoma de Burkitt/epidemiologia , Variações do Número de Cópias de DNA , Perfilação da Expressão Gênica , Genes myc , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/genética , Mutação , Transcriptoma , Translocação GenéticaRESUMO
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
Assuntos
Linfoma de Burkitt/genética , Mutação , Amônia-Liases/genética , Sequência de Bases , Linhagem Celular Tumoral , Chaperonina com TCP-1/genética , DNA Helicases/genética , Proteínas de Ligação a DNA , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Genes myc/genética , Genoma Humano , Glutamato Formimidoiltransferase/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas Inibidoras de Diferenciação/genética , Peptídeos e Proteínas de Sinalização Intracelular , Linfoma Difuso de Grandes Células B/genética , Proteínas de Membrana/genética , Dados de Sequência Molecular , Enzimas Multifuncionais , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-ret/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
Ramoplanin is a lipoglycodepsipeptide antimicrobial active against clinically important Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. To proactively examine ramoplanin resistance, we subjected S. aureus NCTC 8325-4 to serial passage in the presence of increasing concentrations of ramoplanin, generating the markedly resistant strain RRSA16. Susceptibility testing of RRSA16 revealed the unanticipated acquisition of cross-resistance to vancomycin and nisin. RRSA16 displayed phenotypes, including a thickened cell wall and reduced susceptibility to Triton X-100-induced autolysis, which are associated with vancomycin intermediate-resistant S. aureus strains. Passage of RRSA16 for 18 days in a drug-free medium yielded strain R16-18d with restored antibiotic susceptibility. The RRSA16 isolate may be used to identify the genetic and biochemical basis for ramoplanin resistance and to further our understanding of the evolution of antibiotic cross-resistance mechanisms in S. aureus.