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.
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.
Thus, rearrangement at both bcl-1 and PRAD1 loci is strongly associated with centrocytic lymphoma, and provides a useful molecular marker for classifying this subtype of lymphoma.
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.
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.
To compare the expression status of G1 cyclins, these EBV-associated lymphoma lines (6 EBV[-] human SCID mouse lymphoma lines, 13 human B cell lymphomas and 8 samples of human tonsil tissue) were examined by reverse transcription-polymerase chain reaction-Southern blotting, Western blotting and immunohistochemistry. mRNA expression of cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin E (CCNE), cyclin-dependent kinase 2 (CDK2) and 4 (CDK4) was found in all 3 types of lymphomas.
The latter parameters and IPI were the only ones with independent prognostic value (RR = 10, 5.0, 6.7, and 3.7, respectively; P < 0.001) when assessed together with lymphoma sub-type, primary versus relapse cases, treatment, B symptoms, S phase fraction, and presence of BCL1 and BCL2 translocations.
Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types.
In parallel, we investigated the relationship between p27(Kip1), the lymphoma proliferation index, Epstein-Barr virus status, expression of cellular cyclin D3 and cyclin D1, and B-cell differentiation stage.
In human blood cancers, loss of Rb expression has been widely reported in both acute myeloblastic and acute lymphoblastic leukemias, cyclin D1 amplification is common in mantle cell lymphoma, and silencing of the p16/INK4a tumor suppressor gene occurs frequently in AML and various types of lymphoma.
Aberrant Cyclin D1 expression seems to promote proliferation in other types of lymphoma, while a growth promoting CCND1/TACSD1(TROP2) fusion product has also been described in tumors.
Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma.