BCL6

Overview

First described 1993. Earliest sequence paper UniProt cites for the protein: Kerckaert J.-P. et al, Nat. Genet, 1993, "LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas". Source.

Sources: HGNC HGNC:1001 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt P41182 (protein name, function text, keywords and locations (REST API)); CIViC gene BCL6 (2 evidence items, 0 assertions, 2 variants; diseases: Diffuse Large B-cell Lymphoma (GraphQL API, CC0)); Open Targets ENSG00000113916 (association with cancer (MONDO_0004992) 0.63; per-cancer scores at or above 0.5: colorectal cancer 0.52, diffuse large B-cell lymphoma 0.60, non-Hodgkin lymphoma 0.66, skin cancer 0.52, myeloproliferative neoplasm 0.53, lung cancer 0.53 (GraphQL API, CC0)); IntOGen BCL6 (driver in 4 cohorts (Act 2, LoF 2); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)

• Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: IntOGen calls it an activating (Act) driver in 2 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 2 cohorts; CIViC holds 2 clinical evidence items on its variants; UniProt disease notes describe a translocation or gene fusion involving the gene. Evidence tier "clinical-evidence" is the strongest of those signals.
• Prevalence not recorded: none of the sources gives a positivity rate.
• 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).
• Lymphoma, BCL6 and the germinal-centre programme: BCL6 is the master transcriptional repressor of the germinal centre: it switches off the DNA-damage response and the differentiation programme so that a B cell can tolerate deliberate mutation of its own immunoglobulin genes. A lymphoma that keeps BCL6 on keeps a cell in a state where mutation is permitted and apoptosis is suppressed. The protein is normally switched off by acetylation, which is one reason CREBBP and EP300 loss matters here. Frequency: BCL6 rearrangement in 28.7% of 442 diffuse large B-cell lymphomas, the commonest of the three translocations (Horn 2013); BCL6 fusions with NOTCH2 mutations define the BN2 subtype (Schmitz 2018). What it changes about treatment: Nothing yet. There is no approved BCL6 inhibitor or degrader, and the group's prognosis in the genetic classification is comparatively favourable, which is a reason to study de-escalation rather than a reason to change treatment now.