# BCL-2

Source: https://onco.cc/targets/bcl2/  
OnCo record `bcl2` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment.

## Summary

BCL-2 is an anti-apoptotic BH3-domain protein that stops cells from self-destructing; it is overexpressed in more than 90 percent of CLL and, through the t(14;18) translocation, in about 90 percent of follicular lymphomas and 30 to 40 percent of DLBCL. Venetoclax is a BH3 mimetic that occupies the BCL-2 groove and releases the cell-death machinery. It is standard in CLL as fixed-duration therapy with obinutuzumab or ibrutinib and in AML with azacitidine in older patients, where the drug exploits a dependency rather than a measurable expression threshold. Tumour lysis syndrome, managed by ramp-up dosing, and acquired BCL2 mutations are the practical and biological limitations. Next-generation BCL-2 inhibitors (sonrotoclax, lisaftoclax) and MCL-1 inhibitors follow to address resistance. The plain version: venetoclax removes a survival shield and has transformed leukaemia treatment.

## Fields

- Kind: Target
- Last checked: 2026-09-04
- Tags: apoptosis
- Symbol: BCL2
- Class: other
- Biology: BCL-2 is an anti-apoptotic BH3-domain protein, overexpressed via t(14;18) in follicular lymphoma.
- Where found: CLL; AML; Follicular lymphoma; Mantle cell lymphoma

## Notes

- 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).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Bcl-2
- Wikipedia: https://en.wikipedia.org/wiki/Bcl-2
- Tsujimoto et al., Science 1985: the t(14;18) translocation results from a mistake in VDJ joining: https://doi.org/10.1126/science.3929382
- Horn et al., Blood 2013: MYC, BCL2 and BCL6 rearrangement and expression in 442 RICOVER patients: https://doi.org/10.1182/blood-2012-06-435842
- Dalla-Favera et al., PNAS 1982: human c-myc lies in the chromosome 8 region translocated in Burkitt lymphoma: https://doi.org/10.1073/pnas.79.24.7824
- Johnson et al., J Clin Oncol 2012: concurrent MYC and BCL2 protein expression in diffuse large B-cell lymphoma treated with R-CHOP: https://doi.org/10.1200/JCO.2011.41.0985
- Alaggio et al., Leukemia 2022: the fifth edition of the WHO classification of haematolymphoid tumours, lymphoid neoplasms: https://doi.org/10.1038/s41375-022-01620-2

## Connected records

- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Acute myeloid leukaemia in older or unfit patients](https://onco.cc/cancers/aml-older-unfit/), [Blastic plasmacytoid dendritic cell neoplasm (BPDCN)](https://onco.cc/cancers/bpdcn/), [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Chronic lymphocytic leukaemia, first treatment](https://onco.cc/cancers/cll-treatment-naive/), [Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms](https://onco.cc/cancers/cmml/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma)](https://onco.cc/cancers/high-grade-b-cell-lymphoma-myc-bcl2/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/), [Myeloproliferative neoplasms (PV, ET, myelofibrosis)](https://onco.cc/cancers/myeloproliferative-neoplasms/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Relapsed or refractory chronic lymphocytic leukaemia](https://onco.cc/cancers/cll-relapsed/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- technologies: [BCL-2 inhibitors](https://onco.cc/technologies/bcl2-inhibitors/), [BH3 profiling (functional apoptosis testing)](https://onco.cc/technologies/bh3-profiling/), [Senolytics and senescence-directed therapy](https://onco.cc/technologies/senescence-targeting/)
- drugs: [Sonrotoclax](https://onco.cc/drugs/sonrotoclax/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Basal cell carcinoma (KEGG map)](https://onco.cc/pathways/basal-cell-carcinoma-signalling/), [Cellular senescence](https://onco.cc/pathways/senescence/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [Extrinsic apoptosis (death receptors)](https://onco.cc/pathways/extrinsic-apoptosis-death-receptors/), [Ferroptosis & regulated cell death](https://onco.cc/pathways/ferroptosis-cell-death/), [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/), [MicroRNAs in cancer](https://onco.cc/pathways/micrornas-in-cancer/), [Mitosis & the spindle assembly checkpoint](https://onco.cc/pathways/mitotic-spindle-checkpoint/), [MYC](https://onco.cc/pathways/myc/), [Small cell lung cancer (KEGG map)](https://onco.cc/pathways/sclc-signalling/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)
- ideas: [Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain](https://onco.cc/ideas/lymphoma-ev-genetic-subtype-directed-first-line/), [BTK degraders to pre-empt resistance in frontline CLL](https://onco.cc/ideas/idea-btk-degrader-frontline/), [Clear the zombie cells left behind by chemotherapy and radiotherapy](https://onco.cc/ideas/idea-bio1-senolytics-after-therapy/), [One-two punch: clear senescent cells after chemotherapy](https://onco.cc/ideas/idea-senolytics-after-chemo/), [Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)](https://onco.cc/ideas/idea-sclc-subtype-directed/)
- trials: [AMPLIFY](https://onco.cc/trials/amplify/), [CAPTIVATE](https://onco.cc/trials/captivate/), [CELESTIAL-TNCLL](https://onco.cc/trials/celestial-tncll/), [CLL13 / GAIA](https://onco.cc/trials/cll13-gaia/), [CLL14](https://onco.cc/trials/cll14/), [GLOW](https://onco.cc/trials/glow/), [VIALE-A](https://onco.cc/trials/viale-a/)
- pairings: [BTK inhibitor + venetoclax, fixed duration](https://onco.cc/pairings/btki-plus-venetoclax-fixed-duration/), [Venetoclax + obinutuzumab (12 months)](https://onco.cc/pairings/venetoclax-plus-obinutuzumab/)
- terms: [Apoptosis](https://onco.cc/terms/apoptosis/), [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [Cell of origin (GCB vs ABC)](https://onco.cc/terms/cell-of-origin/), [Cell of origin in practice: Hans against expression profiling, and what it changes](https://onco.cc/terms/lymphoma-bio-cell-of-origin-in-practice/), [Double-hit / high-grade B-cell lymphoma](https://onco.cc/terms/double-hit-lymphoma/), [Hallmark: resisting cell death](https://onco.cc/terms/resisting-cell-death/), [LymphGen and the genetic clusters of large B-cell lymphoma](https://onco.cc/terms/lymphoma-bio-lymphgen/), [t(11;14), cyclin D1 and SOX11](https://onco.cc/terms/cyclin-d1-t11-14/), [The germinal centre: why lymphoma starts where antibodies are made](https://onco.cc/terms/lymphoma-bio-germinal-centre/)
- biomarkers: [BCL2 G101V and the other venetoclax binding-site mutations](https://onco.cc/biomarkers/bcl2-g101v/), [BCL2 rearrangement, t(14;18)](https://onco.cc/biomarkers/bcl2-rearrangement/), [Double expressor: MYC and BCL2 protein together by immunohistochemistry](https://onco.cc/biomarkers/myc-bcl2-double-expressor/), [Double-hit and triple-hit: MYC with BCL2 and BCL6 rearrangement](https://onco.cc/biomarkers/double-hit-rearrangement/), [EZH2 gain-of-function mutation (Tyr646, originally Tyr641)](https://onco.cc/biomarkers/ezh2-y646-mutation/)
- key papers: [A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications](https://onco.cc/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/), [AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients](https://onco.cc/key-papers/paper-amplify-acalabrutinib-venetoclax-nejm-2025/), [CLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patients](https://onco.cc/key-papers/paper-cll14-venetoclax-obinutuzumab-nejm-2019/), [Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray](https://onco.cc/key-papers/paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004/), [Genetics and pathogenesis of diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/), [Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes](https://onco.cc/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/), [MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL](https://onco.cc/key-papers/paper-murano-venetoclax-rituximab-nejm-2018/), [The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma](https://onco.cc/key-papers/paper-rosenwald-molecular-profiling-dlbcl-nejm-2002/), [VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy](https://onco.cc/key-papers/paper-viale-a-venetoclax-azacitidine-nejm-2020/)
- roadmaps: [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/)
- people: [Andrew H. Wei](https://onco.cc/people/andrew-wei/), [Anthony Letai](https://onco.cc/people/anthony-letai/), [Barbara Eichhorst](https://onco.cc/people/barbara-eichhorst/), [Constantine S. Tam](https://onco.cc/people/constantine-tam/), [Courtney D. DiNardo](https://onco.cc/people/courtney-dinardo/), [John F. Seymour](https://onco.cc/people/john-seymour/), [Kirsten Fischer](https://onco.cc/people/kirsten-fischer/), [Michael Hallek](https://onco.cc/people/michael-hallek/), [Michael L. Wang](https://onco.cc/people/michael-wang/), [Peter Hillmen](https://onco.cc/people/peter-hillmen/), [William G. Wierda](https://onco.cc/people/william-wierda/)
- institutions: [The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute](https://onco.cc/institutions/osu-james/), [Walter and Eliza Hall Institute of Medical Research](https://onco.cc/institutions/wehi/)
- companies: [Ascentage Pharma](https://onco.cc/companies/ascentage-pharma/)
- targets: [BAX](https://onco.cc/targets/bax/), [BIM (BCL2L11)](https://onco.cc/targets/bim/), [IKZF3 (Aiolos)](https://onco.cc/targets/ikzf3/)

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