Chromosomal translocation
t(14;18)(q32;q21), juxtaposing
BCL2 gene (18q) under the control of the immunoglobulin heavy chain gene promoter (14q), leads to constitutive expression of BCL-2, inhibition of apoptosis and extended cell survival
[45]. Translocation
t(14;18)(q32;q21) is a genetic hallmark of follicular lymphoma (FL) and is detected in approximately 90% of all FL cases. The remainder 10% FL cases lack
BCL2 gene translocation and display distinct molecular features with activated B cell-like, NFκB and proliferation expression profiles and frequent lack of BCL-2 protein expression. Interestingly, no differences in overall survival have been shown between translocation-positive and negative FL cases
[35]. Genetic alterations (chromosomal translocations, gene amplification, and single nucleotide variants) of
BCL2 genes are frequent abnormalities in DLBCL, however, the frequency of distinct alterations, as well as prevalence of BCL-2 positivity differ between the two major COO subtypes. The translocations
t(14;18)(q32;q21), detected in more than 30% GCB DLBCL have been associated with high BCL-2 protein expression and poor outcome
[33]. Interestingly, this chromosomal aberration is not detected in ABC DLBCL
[33][46][33,46]. Amplifications of 18q21 locus resulting in BCL-2 overexpression are in contrary significantly more prevalent in ABC DLBCL and are detected in approximately 20% of ABC DLBCL cases
[34].
BCL2 SNVs can be found in approximately 8% of all DLBCL cases and are more frequently detected in the GCB than in the ABC DLBCL subtype
[33].
BCL2 SNVs usually co-occur with
BCL2 translocation, possibly as a consequence of ongoing aberrant somatic hypermutation
[47]. SNVs tend to be located in the flexible loop domain of
BCL2 gene, while mutations in BH domains that could impact interaction with BH3 mimetics are rare
[47]. Some studies showed that
BCL2 SNVs were associated with shorter progression-free survival while other studies did not
[33][47][33,47]. In mantle cell lymphoma (MCL), BCL-2 protein is overexpressed in virtually all cases. Similarly to ABC DLBCL,
BCL2 amplification is frequently found in MCL, while the translocations are rare
[39]. Another cytogenetic abnormality contributing to high BCL-2 protein expression in MCL is loss of 13q14 locus by deletion
[48]. The cluster at 13q14.3 contains genes for two microRNAs,
miR-15a and
miR-16-1, both of which negatively regulate
BCL2 at the posttranscriptional level. The loss of this chromosomal region thus results in high BCL-2 expression
[49]. Similarly, high BCL-2 protein expression can be documented in virtually all patients with CLL and deletion of 13q14 is common in CLL
[43][50][51][43,50,51]. Another mechanism contributing to high BCL-2 expression in CLL is hypomethylation of
BCL2 gene
[43]. In contrast to the above mentioned B-NHLs, the level of BCL-2 expression in Burkitt lymphoma is low or undetectable, which has been used as a part of the diagnostic algorithm of this lymphoma subtype
[40].