RESUMO
Although follicle center cell (FCC) lymphomas represent mature B cells, a considerable percentage do not have detectable Ig production. We have used Southern blotting and the polymerase chain reaction (PCR) to study the involvement of translocations t(14;18) and t(8;14) in causing defective Ig production in 16 Ig- FCC-derived lymphomas and three Ig- B cell acute lymphoblastic leukemias. In 6 of 19 cases, a t(14;18) was present with the other allele either deleted or in germline. In two cases a t(14;18) and a t(8;14) affected both Ig alleles, as confirmed by karyotyping. In two other cases, rearrangement of both bcl-2 on chromosome 18 and c-myc on chromosome 8 were found as well. Although cytogenetic proof was not available, the latter was probably involved in t(8;14). Restriction map analysis of one more case showed rearrangement on the pseudo-JH3 gene on one allele and t(14;18) on the other. Thus, in 11 of 19 cases, defective Ig H chain production could be explained by the inactivation of both Ig H chain genes due to translocation of one allele, in combination with deletions or defective rearrangements of the other allele. In contrast, in 28 of 30 Ig+ lymphomas, one functional Ig H chain allele was found, either in, or not in, combination with t(14;18). In two cases a single rearranged Ig H chain allele was found in combination with rearrangement of bcl-2. No comigration of the single Ig rearrangement with bcl-2, however, was found both by Southern blotting and PCR, suggesting a variant bcl-2 translocation, which leaves the Ig H chain allele functionally intact.
Assuntos
Linfócitos B/imunologia , Genes de Imunoglobulinas , Imunoglobulinas/biossíntese , Linfoma não Hodgkin/genética , Translocação Genética , Alelos , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 8 , DNA/análise , Enzimas de Restrição do DNA , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulinas/genética , Cariotipagem , Linfoma não Hodgkin/imunologia , Hibridização de Ácido Nucleico , FenótipoRESUMO
During progression of B-lymphoproliferative disorders (B-LPD), increasing divergence can be detected in histology, cytogenetics, and clinical behavior. To investigate genomic tumor cell heterogeneity, 50 biopsies of 21 patients with B-LPD of different histogenetic origin were studied for changes in the immunoglobulin gene structure during follow-up study. Ig-heavy chain (IgH) gene alterations were analyzed by Southern blotting using a panel of eight endonucleases. Ig-light chain (IgL) genes and the translocation of the bc 1-2 gene involved in t(14;18) were also studied. In seven of nine follicular lymphomas, most alterations suggested mutations in the IgH genes. Conservation of most restriction sites and of the t(14; 18) breakpoint confirmed the monoclonal origin in these tumors. Also, in two of three diffuse follicle center cell lymphomas (CLL) and in each of four immunocytomas, IgH alterations were found. In contrast, clonal changes were absent in three centrocytic lymphomas and two cases of CLL. In two follicular lymphomas with bitypic IgL expression, a common origin with subsequent divergence of the two constituents, rather than true biclonality, was indicated by the Ig gene structures. No relation was found between the frequency of somatic mutations and histologic signs of progression. These data indicate that somatic hypermutation in IgH genes is related to the histogenesis of the B-LPD and reflect the physiology of their benign counterparts in normal B cell development.