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.
By Southern blot analysis of single and double digested DNA from placenta and from the tumors, we mapped the breakpoint in BCL-1 to a 0.5 kb Pst-I-HindIII restriction fragment which was approximately 2kb away from the sites of previously mapped breakpoints.
The fact that we never observed amplification of HST & INT-2 independently of BCL-1, which in turn can be amplified solely, suggests the presence, between HST/INT-2 and BCL-1, of a genetic element which could be important in the development of a subset of mammary tumors.
Its overexpression may be a key consequence of rearrangement of the BCL1 vicinity in B-cell neoplasms and a unifying pathogenetic feature in centrocytic lymphoma.
Since D11S287 RNA was present at elevated levels in a group of tumors and cell lines in which the 11q13 region is amplified, it may be the key oncogene on this amplified unit, and could also be activated by BCL-1 translocations.
Thus, bcl-1 and PRAD1 rearrangement is strongly associated with centrocytic lymphoma, providing a useful molecular marker for classifying this subtype of lymphoma and suggesting an important role for PRAD1cyclin D1 in the pathogenesis of this neoplasm.
The mechanism by which deregulated production of cyclin D1/PRAD1, and perhaps other D-type cyclins, contributes to tumor development is only beginning to be deciphered.
Our data suggest that dysregulation of cyclin D1 (a candidate bcl-1, PRAD1 oncogene) can be involved in the pathogenesis of some additional tumor types (e.g., sarcomas and neuroblastomas) besides those reported for amplification and/or mRNA overexpression of this oncogene.(ABSTRACT TRUNCATED AT 250 WORDS)
PRAD1 (previously D11S287) is a putative proto-oncogene at 11q13, activated by overexpression through gene rearrangement or gene amplification in several types of human tumors including parathyroid adenomas, centrocytic lymphomas and other B-cell tumors with t(11;14), and breast cancers.
Thus, PRAD1 likely functions as a direct-acting oncogene whose rearrangement in tumors leads to overexpression or deregulated expression of its normal protein product.
These results constitute additional elements in favor of the role of BCL-1 in lymphoid neoplasia and allow us to speculate about its mechanisms of activation.
These results suggest that the inhibitory effect of RB on cell cycle progression can be abrogated during tumor development either by loss of expression of the RB gene or by increased expression of the cyclin D1 gene.
Cyclin D1 overexpressing cells displayed a decrease in the duration of the G1 phase, decreased cell size, and induced tumors when injected into athymic (nude) mice.
The cyclin D1 (PRAD1, CCND1) gene is affected by translocations and amplification in the genomes of a number of human tumors, suggesting that these changes confer growth advantage on developing tumor cell clones.
Because the less differentiated high grade tumors exhibited a more intense nuclear stain and non-neoplastic epithelial components were not stained, the use of cyclin D1/PRAD1 has potential as a tumor marker.