Diffuse large B-cell lymphomas (DLBL) are a heterogeneous group of lymphomas of aggressive clinical behavior. The majority likely derive from follicular center cells, and roughly one-fifth of large B-cell lymphomas derive from transfor mation of a pre-existing follicular lymphoma. As the name suggests, DLBL has a diffuse histological pattern of large lymphoid cells. Approximately 40% of patients with this disease will be cured. The mainstay of therapy is combination chemotherapy including adriamycin. Some relapsing patients may be rescued by autologous stem cell transplantation following high-dose therapy.
Numerous heterogeneous genetic abnormalities have been reported for DLBL. These lymphomas are not characterized by a single, archetypical translocation, as with the t(14;18) in follicular lymphoma or the t(8;14) of Burkitt's lymphoma. Of the abnormalities that have been identified, those involving the BCL-6 gene at 3q27 are the most common.
BCL-6 was initially described as the gene involved in translocations involving the 3q27 locus in a group of follicular and large B-cell lymphomas. Its expression is often deregulated via translocation with heterologous promoters, including immu-noglobulin promoters. While only 10% of large B-cell lymphomas demonstrate the 3q27 translocation by cytogenetics, gene rearrangements involving 3q27 can be found by Southern hybridization analysis in 40% of large B-cell lymphomas. Additionally, somatic mutation of 5' non-coding sequences has been shown. Overall, BCL-6 expression is found in >80% of DLBL. BCL-6 is required for germinal center formation. Expression of BCL-6 is now used in clinical pathology laboratories as a marker for germinal center origin. Containing six zinc fingers, BCL-6 functions as a transcriptional repressor, at least in part by recruiting histone deacetylases. Likely gene targets of BCL-6 repression include chemokines, cell cycle proteins, and other transcriptional effectors. How repression of the heterogeneous BCL-6 targets leads to oncogenesis is unclear.
Approximately 20% of DLBL have the t(14;18) resulting in BCL-2 expression, which confers a worse prognosis. A significant proportion of these tumors likely arise via transformation of a follicular cell lymphoma. Overexpression of BCL-2 by amplification of the BCL-2 allele has been observed by quantitative Southern hybridization and by comparative genomic hybridization in 11-31% of DLBL cases tested. Other genes which have demonstrated amplification by these techniques include REL, MYC, CDK4 and MDM2.
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