{"entity":{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Bcl-2_family","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Bcl-2_family"},{"label":"Tsujimoto et al., Science 1985: the t(14;18) translocation results from a mistake in VDJ joining","url":"https://doi.org/10.1126/science.3929382"},{"label":"Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax","url":"https://doi.org/10.1158/2159-8290.CD-18-1119"}],"tags":[],"related":[],"cancers":["cll","aml","dlbcl","non-hodgkin-lymphoma","follicular-lymphoma","mantle-cell-lymphoma"],"sections":[],"technologies":[],"targets":["bcl2","tp53","menin","bim","bax"],"drugs":["venetoclax"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-bio-germinal-centre"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"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)."],"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.","nodes":[{"id":"stress","label":"DNA damage, oncogene stress, p53","x":50,"y":5},{"id":"bh3","label":"BH3-only (BIM, PUMA, NOXA)","x":50,"y":22},{"id":"bcl2","label":"BCL-2 / BCL-XL / MCL-1","x":20,"y":42,"targetId":"bcl2"},{"id":"bax","label":"BAX / BAK","x":65,"y":45},{"id":"momp","label":"Mitochondrial permeabilisation","x":65,"y":62},{"id":"cytc","label":"Cytochrome c → caspase-9","x":65,"y":78},{"id":"casp","label":"Caspase-3/7 → apoptosis","x":65,"y":95}],"edges":[{"from":"stress","to":"bh3","type":"activates"},{"from":"bh3","to":"bcl2","type":"inhibits"},{"from":"bh3","to":"bax","type":"activates"},{"from":"bcl2","to":"bax","type":"inhibits"},{"from":"bax","to":"momp","type":"activates"},{"from":"momp","to":"cytc","type":"activates"},{"from":"cytc","to":"casp","type":"activates"}],"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"]},"route":"/pathways/apoptosis-bcl2/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"aml-older-unfit","kind":"cancer","name":"Acute myeloid leukaemia in older or unfit patients","route":"/cancers/aml-older-unfit/"},{"id":"bpdcn","kind":"cancer","name":"Blastic plasmacytoid dendritic cell neoplasm (BPDCN)","route":"/cancers/bpdcn/"},{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cll-treatment-naive","kind":"cancer","name":"Chronic lymphocytic leukaemia, first treatment","route":"/cancers/cll-treatment-naive/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","route":"/cancers/extensive-stage-sclc/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","route":"/cancers/mds/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","route":"/cancers/cll-relapsed/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"target":[{"id":"bax","kind":"target","name":"BAX","route":"/targets/bax/"},{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"bim","kind":"target","name":"BIM (BCL2L11)","route":"/targets/bim/"},{"id":"mcl1","kind":"target","name":"MCL1","route":"/targets/mcl1/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"term":[{"id":"apoptosis","kind":"term","name":"Apoptosis","route":"/terms/apoptosis/"},{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"double-hit-lymphoma","kind":"term","name":"Double-hit / high-grade B-cell lymphoma","route":"/terms/double-hit-lymphoma/"},{"id":"resisting-cell-death","kind":"term","name":"Hallmark: resisting cell death","route":"/terms/resisting-cell-death/"},{"id":"hallmarks-synthesis","kind":"term","name":"Hallmarks of cancer as a synthesis of the theories","route":"/terms/hallmarks-synthesis/"},{"id":"lymphoma-bio-germinal-centre","kind":"term","name":"The germinal centre: why lymphoma starts where antibodies are made","route":"/terms/lymphoma-bio-germinal-centre/"}],"technology":[{"id":"bh3-profiling","kind":"technology","name":"BH3 profiling (functional apoptosis testing)","route":"/technologies/bh3-profiling/"}],"trial":[{"id":"viale-a","kind":"trial","name":"VIALE-A","route":"/trials/viale-a/"}],"pairing":[{"id":"venetoclax-plus-hma","kind":"pairing","name":"Venetoclax + hypomethylating agent","route":"/pairings/venetoclax-plus-hma/"}],"pathway":[{"id":"aml-signalling","kind":"pathway","name":"Acute myeloid leukaemia (KEGG map)","route":"/pathways/aml-signalling/"},{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/"},{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"extrinsic-apoptosis-death-receptors","kind":"pathway","name":"Extrinsic apoptosis (death receptors)","route":"/pathways/extrinsic-apoptosis-death-receptors/"},{"id":"ferroptosis-cell-death","kind":"pathway","name":"Ferroptosis & regulated cell death","route":"/pathways/ferroptosis-cell-death/"},{"id":"micrornas-in-cancer","kind":"pathway","name":"MicroRNAs in cancer","route":"/pathways/micrornas-in-cancer/"},{"id":"mitotic-spindle-checkpoint","kind":"pathway","name":"Mitosis & the spindle assembly checkpoint","route":"/pathways/mitotic-spindle-checkpoint/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"},{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"},{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","route":"/pathways/p53-mdm2-axis/"}],"biomarker":[{"id":"bcl2-g101v","kind":"biomarker","name":"BCL2 G101V and the other venetoclax binding-site mutations","route":"/biomarkers/bcl2-g101v/"},{"id":"bcl2-rearrangement","kind":"biomarker","name":"BCL2 rearrangement, t(14;18)","route":"/biomarkers/bcl2-rearrangement/"},{"id":"myc-bcl2-double-expressor","kind":"biomarker","name":"Double expressor: MYC and BCL2 protein together by immunohistochemistry","route":"/biomarkers/myc-bcl2-double-expressor/"},{"id":"double-hit-rearrangement","kind":"biomarker","name":"Double-hit and triple-hit: MYC with BCL2 and BCL6 rearrangement","route":"/biomarkers/double-hit-rearrangement/"}],"roadmap":[{"id":"lymphoma-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/lymphoma-roadmap/"}],"person":[{"id":"anthony-letai","kind":"person","name":"Anthony Letai","route":"/people/anthony-letai/"}],"idea":[{"id":"idea-bio1-senolytics-after-therapy","kind":"idea","name":"Clear the zombie cells left behind by chemotherapy and radiotherapy","route":"/ideas/idea-bio1-senolytics-after-therapy/"},{"id":"idea-senolytics-after-chemo","kind":"idea","name":"One-two punch: clear senescent cells after chemotherapy","route":"/ideas/idea-senolytics-after-chemo/"}]}}