Detection of BCL2 Rearrangements in Follicular Lymphoma

The identification and characterization of recurrent chromosomal translocations has improved tumor classification and yielded numerous insights into tumor pathogenesis, as such events typically lead to the dysregulation of proteins that control critical cellular processes, such as apoptosis, proliferation, differentiation, and immortalization. A prototypical example of such a chromosomal translocation is the (14;18)(q32;q32), which is highly associated with the B cell neoplasm follicular lymphoma. 1 Molecular analyses of DNA isolated from follicular lymphoma cells in the mid-1980’s showed that the t(14;18) creates a derivative chromosome 14 on which the BCL2 gene is juxtaposed to immunoglobulin heavy chain gene (IgH) sequences, 2-5 including enhancer sequences that override normal BCL2 gene control elements and drive inappropriately high levels of BCL2 expression in follicle center B cells. 6,7 Subsequently, several groups noted that enforced expression of BCL2 transgenes in murine hematopoietic cells promoted cell survival, 8,9 the first indication of the anti-apoptotic activity of BCL2. BCL2 transgenic mice also showed increased susceptibility to autoimmune disease 10 and B cell lymphoma, 11 observations that helped to foster the now generally accepted idea that dysregulation of apoptotic pathways is important in the pathogenesis of many forms of cancer and autoimmune disorders. These effects of BCL2 appear to be mediated through sequestration of “BH3 domain only” pro-apoptotic proteins such as BAD, BIM, and NOXA, 12 which resets the apoptotic “rheostat” toward increased resistance to programmed cell death. In addition to its impact on our thinking about cancer pathophysiology, the molecular characterization of the t(14;18) and its downstream consequences has influenced our approach to the diagnosis of hematological malignancy in several ways. The t(14;18) was an early example of an acquired genetic lesion that was strongly associated with a particular neoplasm, and thus of utility in tumor classification. Juxtaposed BCL2 and IgH DNA sequences provide a tumor-specific marker that can be exploited in the detection of minimal residual disease. 13,14 Furthermore, because BCL2 is down-regulated in normal germinal center B cells, 15 its expression (or lack thereof) can help to distinguish reactive and neoplastic follicles. 16 Finally, the presence of the t(14;18) has been suggested to be a marker of poor prognosis in diffuse large B cell lymphoma 17,18 (possibly because some such tumors arise through transformation of unrecognized underlying follicular lymphomas), although it must be said that more recent studies have not detected such a correlation. 19-21 These relationships have prompted the development of multiple methods that aim to detect the t(14;18) in tissue specimens. In this issue of The American Journal of Pathology, Albinger-Hegyi et al 22 report a new set of polymerase chain reaction (PCR)-based tests for detection of the BCL2/IgH fusion genes that offer some significant advantages in sensitivity over other more commonly used PCR-based methods. This commentary will attempt to place this contribution in context by discussing the advantages and limitations of various tests that aim to detect the t(14;18) or its downstream consequences.