RESUMO
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)âPI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCRâNF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17â¼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCRâPI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.
Assuntos
Linfoma de Burkitt/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Imunofenotipagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Adulto JovemRESUMO
The pandemic (H1N1) 2009 virus is unique in many aspects, especially in its genetics and evolution. In this paper, we examine the molecular mechanisms underlying the evolution of this novel virus through a comprehensive bioinformatics analysis, and present results in the context of a review of the literature. The pandemic virus was found to arise from a reassortment of two swine viruses, each of which ultimately arose from interspecies transmission. It experienced fast evolutionary rates and strong selection pressures, diverging into two different clusters at the early pandemic stage. Cluster I became extinct at the end of 2009 whereas Cluster II continued to circulate at much lower rates in 2010. Therefore, on August 10 of 2010 the WHO declared the end of the pandemic. Important mutations associated with host specificity, virulence, and drug resistance were detected in the pandemic virus, indicating effective transmission and increased severity in humans. Much has been learned about the evolutionary dynamics of this pandemic virus; however, it is still impossible to predict when the next pandemic will occur and which virus will be responsible. Improved surveillance at different levels (both national and international) and in different hosts (especially in swine) appears to be crucial for early detection and prevention of future influenza pandemics.