The probe appears to identify bcl-2, a gene locus on chromosome 18 (band q21) that is unrelated to known oncogenes and may be important in the pathogenesis of B-cell neoplasms with this translocation.
We have cloned the chromosomal joinings between chromosomes 11 and 14 and also between chromosomes 14 and 18, in B-cell tumours carrying translocations involving these chromosomes, and suggested the existence of two translocated loci, bcl-1 and bcl-2, normally located on chromosomes 11 (band q13) and 18 (band q21) respectively, involved in the pathogenesis of human B-cell neoplasms.
However, because performing accurate cytogenetic studies in solid hematolymphoid neoplasms is difficult, knowledge of the prevalence of the t(14;18) translocation and, by association, the extent of bcl-2 involvement in human lymphomas is limited.
Every tumor with molecular-genetic evidence of t(14;18) translocation expressed detectable levels of bcl-2 protein, regardless of whether the breakpoint was located in or at a distance from the bcl-2 gene.
These data indicate that primary cutaneous lymphomas of B-cell origin share morphological and phenotypic similarities with the nodal B-cell lymphomas of follicular histotype, are proliferating, and express in 45% of cases clear monoclonal immunoglobulin light chain; the molecular analysis confirms the B-cell derivation and the monoclonal nature of this neoplasia; it also shows that neither bcl-2 nor c-myc oncogenes are involved and that no inappropriate rearrangements of the T-cell receptor genes are found in this lymphoma.
Moreover, a BCL2 antisense expression plasmid ablated tumor formation by Jurkat cells, providing further evidence that this oncogene contributes to the regulation of the in vivo growth of these human T lymphocytes.
In addition to NBs, lower levels of BCL2 protein were also found in a variety of other neural crest-derived tumors and tumor cell lines, including some neuroepitheliomas, Ewing's sarcomas, neurofibromas, and melanomas.
Immunohistochemical studies employing a highly specific anti-Bcl-2 antiserum under conditions optimized to detect t(14;18)-mediated overexpression of the Bcl-2 gene showed that the Reed-Sternberg cells and variants in all 19 HD tumors examined were negative forBcl-2 immunostaining.
Additionally, almost all lymphomas with a t(14;18) versus 41% of the tumors without a bcl-2 rearrangement presented with lymphadenopathy. c-myc rearrangements were seen in 35% of the extranodal lymphomas and 5% of the nodal lymphomas.
Presence of bcl-2 protein in nodal large-cell lymphomas seems to be independent of a t(14;18) translocation, only being found in 19 to 28% of these lymphomas, although it constitutes a definite difference between both tumors, suggesting the existence of different molecular genetic characteristics and pathogenesis, and is possibly related to the more aggressive clinical behavior of nodal high-grade tumors.
DNA sequencing determined that these mutations are predicted to produce aa substitutions in the BCL2 proteins of two of the primary tumors and one of the cell lines.
A translocation involving the bcl-2 gene on chromosome 18 and the immunoglobulin heavy chain gene on chromosome 14 is frequently found in follicular lymphomas and is believed to play a critical role in the pathogenesis of these tumors.
Unexpectedly, dissimilar immunoglobulin light and heavy chain gene rearrangements were detected in the paired samples from one patient with previously diagnosed follicular lymphoma, making the relationship of the two tumors from this patient uncertain; however, additional Southern blot analysis of the bcl-2 gene showed identical rearrangements in both lesions.
The relation between bcl-2 protein expression and survival was small, depending on the primary localisation of the tumour (in lymph node of mucosae), and lacked a significant correlation with overall survival.
In univariate analysis, Bcl-2 and p53 expression, [3H]thymidine-labeling index, tumor size, and ER status were indicators for relapse-free and, with the exception oftumor size, overall survival within 6 years of surgery.
The degree and pattern of staining suggest a loss of bcl-2 expression with tumor maturity in keratoacanthoma and a possible role in their ultimate involution.
Southern blot hybridization analysis failed to show evidence of bcl-1, bcl-2, c-myc proto-oncogene or retinoblastoma (Rb) tumor-suppressor gene rearrangements in these six cases of Richter's syndrome.
Detection of tumor cells in purged bone marrow and peripheral-blood mononuclear cells by polymerase chain reaction amplification of bcl-2 translocations.