BCL-2

Overview

First described 1986. Earliest sequence paper UniProt cites for the protein: Tsujimoto et al, Proc. Natl. Acad. Sci. U.S.A, 1986, "Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma". Source.

• Lymphoma, BCL2 and t(14;18): The t(14;18) translocation puts BCL2 under the control of the immunoglobulin heavy-chain enhancer, so the cell makes an anti-apoptotic protein at a level a germinal-centre B cell is never meant to have. The sequencing of the breakpoints showed that the translocation is a mistake made by the VDJ recombinase at the pre-B-cell stage: the chromosome 18 segment recombines with the JH segment on chromosome 14, with extraneous N-region nucleotides at the junction and signal-like sequences near the chromosome 18 breakpoint (Tsujimoto 1985). The lesion is therefore not a late event in a lymphoma but the first event, made in the bone marrow years before. Frequency: BCL2 rearrangement in 13.5% of 442 unselected diffuse large B-cell lymphomas in the RICOVER trial (Horn 2013), and in the large majority of follicular lymphomas. A t(14;18)-bearing B cell can be found in the blood of healthy people, so the translocation alone is not a disease. What it changes about treatment: Less than it should. Venetoclax, which displaces the pro-apoptotic partners from BCL-2 directly, transformed chronic lymphocytic leukaemia and has not transformed follicular or diffuse large B-cell lymphoma, where the cells also depend on MCL1 and BCL-xL. A BCL2 rearrangement is used for diagnosis and, in combination with MYC, for risk, not for drug choice.
• Lymphoma, MYC, and the double-hit and triple-hit definitions: MYC was mapped to 8q24, the region translocated to chromosome 2, 14 or 22 in Burkitt lymphoma cells, in 1982 (Dalla-Favera 1982); the partner is always an immunoglobulin locus, so the transcription factor is driven by the enhancer that should be driving antibody production. A double hit is a MYC rearrangement together with a BCL2 rearrangement, a triple hit adds BCL6. The two lesions are complementary rather than additive: MYC drives proliferation and would normally trigger apoptosis, and BCL2 removes that safeguard. Frequency: MYC rearrangement in 8.8% of 442 diffuse large B-cell lymphomas, BCL2 in 13.5% and BCL6 in 28.7% (Horn 2013). Protein overexpression is much commoner than rearrangement: MYC protein above the 40% threshold in 31.8% of the same cohort (Horn 2013), and in a separate 167-patient training cohort MYC protein in 29%, BCL2 protein in 44% and both together in 21%, against MYC translocation in only 11% (Johnson 2012). What it changes about treatment: The WHO fifth edition separates high-grade B-cell lymphoma with MYC and BCL2 rearrangements as its own entity (Alaggio 2022), and in practice a double hit moves most patients off R-CHOP onto a more intensive regimen, although the randomised evidence for doing so is thin. Double expression of the two proteins without rearrangement is prognostic, not a separate entity, and does not by itself change the regimen: in the trial cohort MYC protein predicted worse survival only when BCL2 protein was present too (Johnson 2012).