# Intrinsic apoptosis (BCL-2 family)

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

## TL;DR

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.

## Summary

Stress signals induce BH3-only proteins (BIM, PUMA, NOXA, BAD) that either inhibit anti-apoptotic BCL-2, BCL-XL, MCL-1 or directly activate BAX/BAK, which permeabilise the mitochondrial outer membrane, releasing cytochrome c to activate caspase-9 and executioner caspases. Cancers overexpress BCL-2 (t(14;18) in follicular lymphoma; CLL), MCL-1 (myeloma, AML), or BCL-XL (solid tumours, platelets). Venetoclax (BCL-2) transformed CLL and AML; MCL-1 inhibitors have cardiac toxicity; BCL-XL degraders and platelet-sparing PROTACs are in development.

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: A dam (mitochondrial membrane) held by guards (BCL-2, MCL-1) against demolition crews (BAX/BAK). Cancer hires extra guards. Venetoclax fires the BCL-2 guards, and the dam breaks.
- Interventions: Venetoclax (BCL-2) in CLL, AML, mantle cell lymphoma; Next-generation BCL-2 inhibitors sonrotoclax, lisaftoclax; MCL-1 inhibitors (limited by cardiotoxicity); BCL-XL PROTACs sparing platelets; Combinations with hypomethylating agents, BTK inhibitors, menin inhibitors

## Notes

- Lymphoma: the founding lesion of follicular lymphoma is a recombination accident. The t(14;18) breakpoints carry N-region nucleotides and sit beside signal-like sequences, which identifies the translocation as a mistake by the VDJ recombinase at the pre-B-cell stage rather than a late event (Tsujimoto 1985). Venetoclax has not repeated its chronic lymphocytic leukaemia result in lymphoma, because these cells also lean on MCL1 and BCL-xL, and the escape mutation when it does work, BCL2 G101V, lowers drug affinity about 180-fold and appears months before clinical progression (Blombery 2019).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Bcl-2_family
- Wikipedia: https://en.wikipedia.org/wiki/Bcl-2_family
- Tsujimoto et al., Science 1985: the t(14;18) translocation results from a mistake in VDJ joining: https://doi.org/10.1126/science.3929382
- Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax: https://doi.org/10.1158/2159-8290.CD-18-1119

## 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/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Extensive-stage small-cell lung cancer](https://onco.cc/cancers/extensive-stage-sclc/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/), [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/)
- targets: [BAX](https://onco.cc/targets/bax/), [BCL-2](https://onco.cc/targets/bcl2/), [BIM (BCL2L11)](https://onco.cc/targets/bim/), [MCL1](https://onco.cc/targets/mcl1/), [Menin](https://onco.cc/targets/menin/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Azacitidine](https://onco.cc/drugs/azacitidine/), [Sonrotoclax](https://onco.cc/drugs/sonrotoclax/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- terms: [Apoptosis](https://onco.cc/terms/apoptosis/), [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [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/), [Hallmarks of cancer as a synthesis of the theories](https://onco.cc/terms/hallmarks-synthesis/), [The germinal centre: why lymphoma starts where antibodies are made](https://onco.cc/terms/lymphoma-bio-germinal-centre/)
- technologies: [BH3 profiling (functional apoptosis testing)](https://onco.cc/technologies/bh3-profiling/)
- trials: [VIALE-A](https://onco.cc/trials/viale-a/)
- pairings: [Venetoclax + hypomethylating agent](https://onco.cc/pairings/venetoclax-plus-hma/)
- pathways: [Acute myeloid leukaemia (KEGG map)](https://onco.cc/pathways/aml-signalling/), [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Cellular senescence](https://onco.cc/pathways/senescence/), [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [Extrinsic apoptosis (death receptors)](https://onco.cc/pathways/extrinsic-apoptosis-death-receptors/), [Ferroptosis & regulated cell death](https://onco.cc/pathways/ferroptosis-cell-death/), [MicroRNAs in cancer](https://onco.cc/pathways/micrornas-in-cancer/), [Mitosis & the spindle assembly checkpoint](https://onco.cc/pathways/mitotic-spindle-checkpoint/), [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/)
- 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/)
- 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: [Anthony Letai](https://onco.cc/people/anthony-letai/)
- ideas: [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/)

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JSON: https://onco.cc/api/v1/entities/apoptosis-bcl2.json