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.
It was shown that bcl-2 gene rearrangements were exclusively confined to centroblastic-centrocytic lymphomas. bcl-1 rearrangements were found in two cases of chronic lymphocytic leukaemia.
These results indicate that rearrangement of the BCL1 locus may be closely associated with ILL and could be considered as a genotypic marker of this lymphoma subtype.
Immunohistochemical expression of PRAD1/cyclin D1 protein has been investigated in 106 tissue specimens of 104 cases of lymphoma, non-neoplastic lymphoid disorders and other hematologic malignancies by employing the monoclonal antibody 5D4 with formalin-fixed paraffin-embedded sections, using the microwave oven heating method.
These results indicated that positive nuclear staining of lymphoma cells by 5D4 antibody reflects PRAD1/cyclin D1 mRNA expression, and showed that this monoclonal antibody has diagnostic value for differentiating MCL from other types of lymphomas.
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.
CYCLIN D1, a cell-cycle control gene, recently has been shown to be identical to an oncogene alternatively known as BCL-1 and PRAD1 and implicated in centrocytic lymphomas and parathyroid adenomas, respectively.
The coincidence of anaplastic and sometimes blast-like morphology of the tumour cells, high proliferation index and a rearranged bcl-1 gene in nearly all cases of anaplastic centrocytic lymphoma support their classification as high-grade malignant variants of centrocytic lymphoma and suggest a possible role for the bcl-1 locus not only in the origin but also in the progression of centrocytic lymphomas.
Rearrangements at the chromosome 11q13 bcl-1 breakpoint loci are present in the majority of these lymphomas, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain joining genes.
The PRAD1 gene, located at 11q13, has been implicated in the pathogenesis of a variety of tumors, including parathyroid adenomas, t(11;14) bearing B-lymphoid tumors (particularly centrocytic lymphomas) where it is highly likely to be the BCL1 oncogene, and possibly in breast carcinomas and squamous cell cancers of the head and neck as well.
Cyclin D1, an oncogene that has a critical role in G1 progression of the cell cycle, has been observed to be amplified in carcinomas of the breast and head and neck, and translocated in parathyroid adenomas and centrocytic lymphomas.
In particular, the recognition of chromosomal translocations which have activated the BCL1 and BCL2 proto-oncogenes have strong associations with specific types of non-Hodgkin's malignant lymphomas such as mantle cell lymphoma and follicular center cell lymphoma, respectively.
Lymphoma cell lines harboring the t(11;14) showed cyclin D1 protein but no or very low levels of cyclin D3; three other B-cell lines, a T-cell line, and peripheral blood lymphocytes strongly expressed cyclin D3 and reacted negatively for cyclin D1.
The contribution of other chromosomal abnormalities other than bcl-1 and bcl-2 rearrangements in the pathogenesis of MCL and follicular-cell lymphomas has to be determined.
We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry.
In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level.