Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Folicular/mortalidade , Linfoma Folicular/terapia , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/imunologia , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 18/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Taxa de Sobrevida , Translocação Genética/genética , Translocação Genética/imunologia , Transplante Homólogo , Estados Unidos/epidemiologiaRESUMO
Human germinal center B cell tumors retain the ability of their nontransformed counterparts to somatically hypermutate Ig V genes by nucleotide substitution. Among a survey of 60 primary previously untreated, clonal, follicular lymphomas we have identified a rare V(H) rearrangement variant and two other in-frame nucleotide insertion/deletion variants within complementarity-determining region III of the Ig heavy chain. The neoplastic origin of the V(H) rearrangement variant was directly demonstrated in cells isolated by microdissection from malignant follicles. In all three cases a common clonal origin for the variants was demonstrated by complementarity-determining region III nucleotide sequence homology and shared somatic mutations in germline encoded positions in framework region IV. The monoclonal nature of the tumors was independently confirmed by demonstrating a single t(14;18) translocation breakpoint in the two cases with a detectable translocation. All the variants occurred in functional V(H) rearrangements, which in two cases were directly shown to encode functional Ab molecules. Both recombination-activating genes 1 and 2 were expressed in lymph node tumor cells containing the V(H) rearrangement variant, although recombination-activating gene expression among a panel of lymphomas was not limited to this variant.
Assuntos
Regiões Determinantes de Complementaridade/genética , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Mutagênese Insercional/imunologia , Fases de Leitura/imunologia , Deleção de Sequência/imunologia , Sequência de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Sequência de Bases , Separação Celular , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/imunologia , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 18/imunologia , Células Clonais , Regiões Determinantes de Complementaridade/biossíntese , Impressões Digitais de DNA , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Amplificação de Genes , Genes de Imunoglobulinas , Variação Genética/imunologia , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Humanos , Cadeias J de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Linfoma Folicular/patologia , Dados de Sequência Molecular , Proteínas Nucleares , RNA Mensageiro/biossíntese , Fases de Leitura/genética , Análise de Sequência de DNA , Translocação Genética , Transposases/genéticaRESUMO
Human TRAF-3 is a signaling molecule that interacts with the cytoplasmic tails of CD40 and other TNF-receptor family members. TRAF-3 mRNA is expressed as two major classes of approximately 2 and 8 kb and a number of TRAF-3 encoding cDNA clones differ in discrete gene segments. Because this variety of mRNA species could result from mRNA processing events and/or multiple genes, the structure and localization of TRAF-3 encoding gene elements were determined. FISH and radiation hybrid mapping demonstrated that TRAF-3 is located at chromosome 14q32.3, approximately 1 Mb centromeric to the Ig heavy chain gene complex. Physical mapping of four overlapping genomic PAC clones established that TRAF-3 transcripts are encoded by a single gene, comprised of 13 exons and spanning 130 kb. Alternative polyadenylation in the mRNA segment encoded by exon 12 accounts for the difference between the 2 kb and the 8 kb classes of transcripts. Alternative mRNA splicing in the coding region (encoded by exons 3-12) generates transcripts which delete exons 8 (75 nt), 7+8 (156 nt) or 8+9 (168 nt) and that encode distinct protein isoforms (delta25, delta52 and delta56 aa, respectively). Alternative splicing of exon 2 (139 nt) and alternative transcriptional initiation result in mRNA species with distinct 5'UTRs. Together, these data indicate that a single TRAF-3 gene encodes a variety of mRNA species by a combination of alternative polyadenylation, alternative mRNA splicing and/or alternative initiation.
