BCL-2
A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment. This dossier gathers the 2 products (2 approved), 10 trials, 8 pathways and 0 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
BCL-2 is an anti-apoptotic BH3-domain protein, overexpressed via t(14;18) in follicular lymphoma.
- CLL
- AML
- Follicular lymphoma
- Mantle cell lymphoma
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Chronic lymphocytic leukaemia | >90% | BCL-2 overexpression | Wikipedia | |
| Diffuse large B-cell lymphoma | 30-40% | BCL2 translocation/overexpression | ~90% in follicular lymphoma t(14;18) | Wikipedia |
| Acute myeloid leukaemia | n/a | Dependency, not a prevalence threshold | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| G101V 101 | Resistance | not sourced | Reduces venetoclax affinity about 180-fold; found in a subset of CLL relapsing on continuous venetoclax, often subclonal. Sonrotoclax is reported to retain activity against it. | Blombery et al., Cancer Discov 2019 | ||
| D103Y / F104L 103 | Resistance | not sourced | Additional BH3-groove mutations co-occurring with G101V. | Blombery et al., Cancer Discov 2019 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: COSMIC: BCL2.
Products by modality and phase
Browse products →| Modality | Approved |
|---|---|
| Small molecule 2 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| AMPLIFY NCT03836261 | 3 | Positive | Fit, previously untreated CLL without del(17p)/TP53: fixed-duration acalabrutinib + venetoclax (AV) or + obinutuzumab (AVO) vs FCR/BR chemoimmunotherapy | 3-year PFS 76.5% (AV) / 83.1% (AVO) vs 66.5%. | |
| CLL13 / GAIA NCT02950051 | 3 | Positive | Fit, previously untreated CLL without del(17p)/TP53: chemoimmunotherapy (FCR/BR) vs venetoclax-rituximab vs venetoclax-obinutuzumab vs venetoclax-obinutuzumab-ibrutinib | 5-year PFS 81.3% (GIV), 69.8% (GV), 57.4% (RV), 50.7% (CIT). | |
| SEQUOIA NCT03336333 | 3 | Positive | Previously untreated CLL/SLL unsuitable for FCR: zanubrutinib vs bendamustine-rituximab (cohort 1); zanubrutinib in del(17p) (arm C); zanubrutinib + venetoclax (arm D) | PFS HR 0.42 vs BR; 5-year PFS 72.2% in del(17p). | |
| GLOW NCT03462719 | 3 | Positive | Previously untreated CLL, age ≥65 or with comorbidities, no del(17p)/TP53: fixed-duration ibrutinib + venetoclax vs chlorambucil + obinutuzumab | PFS HR 0.216; OS HR 0.487 (4-year). | |
| VIALE-A NCT02993523 | 3 | Positive | Newly diagnosed AML unfit for intensive chemotherapy: venetoclax + azacitidine vs placebo + azacitidine | OS 14.7 vs 9.6 months, HR 0.66; CR 36.7% vs 17.9%. | |
| CLL14 NCT02242942 | 3 | Positive | Previously untreated CLL with coexisting conditions: 12 months of venetoclax + obinutuzumab vs chlorambucil + obinutuzumab | 6-year PFS 53.1% vs 21.7%; HR 0.40. | |
| CELESTIAL-TNCLL NCT06073821 | 3 | Active | Previously untreated CLL/SLL: fixed-duration sonrotoclax + zanubrutinib vs venetoclax + obinutuzumab | ||
| myeloMATCH NCT05564390 | platform | Recruiting | Newly diagnosed AML and MDS: genomic screening at diagnosis assigns patients to tiered, biomarker-defined sub-studies from induction through MRD-guided consolidation and maintenance | ||
| ASCERTAIN-V NCT04657081 | 2 | Positive | Newly diagnosed AML unfit for intensive induction: oral decitabine-cedazuridine + venetoclax | CR 41.6%; median time to CR 2 months. | |
| CAPTIVATE NCT02910583 | 2 | Positive | Previously untreated CLL, age ≤70: 3 cycles ibrutinib lead-in then 12 cycles ibrutinib + venetoclax (fixed-duration cohort n=159; MRD-guided cohort n=164) | CR 55%; uMRD 77%; 4-year PFS ~79%. |
Resistance routes that involve this target
Unaddressed routes →The resistance atlas has no route that names this target.
Pathways where it is a node
Pathway-to-drug matrix →- B-cell receptor / BTK signalling (to NF-κB)Node: BCL2, IL-6, IL-10, cyclin D → survival · 1 druggable nodes
The B-cell receptor is the survival switch of B cells. Signals from it pass through BTK to free NF-kappa-B, which keeps the cell alive. B-cell cancers hold it on; BTK inhibitors, proteasome inhibitors and lenalidomide each cut the line at a different point.
Which nodes have drugs → - Drug-tolerant persister cellsNode: Efflux, autophagy, BCL-XL · 3 druggable nodes
Even when a drug wipes out 99% of a tumour, a few cells survive without any resistance mutation: they go quiet, stop dividing, and wait. These persisters are the seed of relapse. They are hard to kill precisely because they are not doing much, but they have their own weaknesses.
Which nodes have drugs → - Extrinsic apoptosis (death receptors)Node: tBID → mitochondria · 2 druggable nodes
Immune cells kill by touch: they present FAS ligand or TRAIL to a target cell, whose death receptors then trigger self-destruction from the outside in. Tumours cut this wire by deleting the receptors or over-producing decoys and blockers.
Which nodes have drugs → - Ferroptosis & regulated cell deathNode: Apoptosis (BCL-2 family) · 1 druggable nodes
Cells can die in several programmed ways. Beyond the classic apoptosis, ferroptosis kills through iron-driven fat oxidation, and drug-resistant, mesenchymal cancer cells turn out to be unusually prone to it.
Which nodes have drugs → - Intrinsic apoptosis (BCL-2 family)Node: BCL-2 / BCL-XL / MCL-1 · 1 druggable nodes
Intrinsic apoptosis is the cell's self-destruct switch. BCL-2 holds it shut; BAX and BAK pull it open. Venetoclax pries BCL-2 off so the switch can fire.
Which nodes have drugs → - Mitosis & the spindle assembly checkpointNode: Mitotic death (BCL-XL↓) · 3 druggable nodes
When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
Which nodes have drugs → - The p53 network (guardian of the genome)Node: PUMA, NOXA → apoptosis · 4 druggable nodes
p53 is the cell's emergency coordinator. Damage, oncogene stress, or lack of oxygen switch it on; it then pauses division, orders repairs, or triggers suicide or permanent retirement. MDM2 keeps it switched off in healthy cells. Half of all cancers break p53 outright; many of the rest over-produce MDM2.
Which nodes have drugs → - Transcriptional machinery & addictionNode: MYC, MCL-1 (short-lived) · 4 druggable nodes
Cancer cells run a few genes (MYC, their lineage factors, their fusion oncogenes) at extreme volume from giant control regions called super-enhancers. The amplifiers, BRD4, CDK7, CDK9 and Mediator, are the same in every cell, but cancers are unusually dependent on them, and that dependence is druggable.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →No companion diagnostic in the registry measures this target.
Preclinical models
All models →No model entry for this target yet; check the cancer entries on the models page.
Open questions
All open questions →- 01
Is fixed-duration venetoclax-based therapy curative for a subset of CLL, and who needs retreatment?
clinicalclinicWhy unresolved. CLL14 and AMPLIFY show long treatment-free remissions after one or two years; measurable-residual-disease kinetics predict relapse but retreatment strategies and the role of newer BCL2 inhibitors are unsettled.
What would answer it. Long-term follow-up with MRD-guided retreatment trials and comparison of sonrotoclax with venetoclax.
Source: CLL14, NEJM 2019
Ideas and companies
Key papers and the live literature
Preprints →- AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients · New England Journal of Medicine 2025
- VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy · New England Journal of Medicine 2020
- CLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patients · New England Journal of Medicine 2019
- MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL · New England Journal of Medicine 2018
Query for this target: (TITLE:"BCL-2" OR ABSTRACT:"BCL-2" OR TITLE:"BCL2" OR ABSTRACT:"BCL2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BCL-2, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/bcl2.json. Licence CC BY 4.0.