{"entity":{"id":"bcl2","kind":"target","name":"BCL-2","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Bcl-2","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Bcl-2"},{"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":"Horn et al., Blood 2013: MYC, BCL2 and BCL6 rearrangement and expression in 442 RICOVER patients","url":"https://doi.org/10.1182/blood-2012-06-435842"},{"label":"Dalla-Favera et al., PNAS 1982: human c-myc lies in the chromosome 8 region translocated in Burkitt lymphoma","url":"https://doi.org/10.1073/pnas.79.24.7824"},{"label":"Johnson et al., J Clin Oncol 2012: concurrent MYC and BCL2 protein expression in diffuse large B-cell lymphoma treated with R-CHOP","url":"https://doi.org/10.1200/JCO.2011.41.0985"},{"label":"Alaggio et al., Leukemia 2022: the fifth edition of the WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"}],"tags":["apoptosis"],"related":[],"cancers":["cll","aml","dlbcl","non-hodgkin-lymphoma"],"sections":[],"technologies":["bcl2-inhibitors"],"targets":[],"drugs":["sonrotoclax","venetoclax"],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2","basal-cell-carcinoma-signalling","micrornas-in-cancer","sclc-signalling","myc","transcription-addiction"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"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)."],"symbol":"BCL2","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"few-types","specificityNote":"Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 2 medicines aimed at it (Sonrotoclax, Venetoclax) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA BCL2: RNA low tissue specificity; blood lineage group enriched (B-cells 5 nTPM, T-cells 9 nTPM); high antibody staining in 18 normal tissues; highest cancer staining lymphoma (7 of 12 high). Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Leukaemia, Lymphoma); Open Targets associates it with 5 specific cancer types at or above 0.5 (B-cell chronic lymphocytic leukemia, diffuse large B-cell lymphoma, prostate carcinoma, acute myeloid leukemia, lymphoid leukemia). (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas BCL2 tissue","url":"https://www.proteinatlas.org/ENSG00000171791-BCL2/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000171791 associations","url":"https://platform.opentargets.org/target/ENSG00000171791/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:990","ensembl":"ENSG00000171791","uniprot":"P10415","entrez":"596","firstDescribed":1986,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Tsujimoto et al, Proc. Natl. Acad. Sci. U.S.A, 1986, \"Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/3523487/","biology":"BCL-2 is an anti-apoptotic BH3-domain protein, overexpressed via t(14;18) in follicular lymphoma.","whereFound":["CLL","AML","Follicular lymphoma","Mantle cell lymphoma"],"targetClass":"other","prevalence":[{"cancerId":"cll","pct":">90","measure":"BCL-2 overexpression","source":"https://en.wikipedia.org/wiki/Bcl-2"},{"cancerId":"dlbcl","pct":"30-40","measure":"BCL2 translocation/overexpression","source":"https://en.wikipedia.org/wiki/Bcl-2","note":"~90% in follicular lymphoma t(14;18)"},{"cancerId":"aml","pct":"n/a","measure":"Dependency, not a prevalence threshold","source":"https://en.wikipedia.org/wiki/Bcl-2"}]},"route":"/targets/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":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"high-grade-b-cell-lymphoma-myc-bcl2","kind":"cancer","name":"High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma)","route":"/cancers/high-grade-b-cell-lymphoma-myc-bcl2/"},{"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":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"},{"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/"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}],"technology":[{"id":"bcl2-inhibitors","kind":"technology","name":"BCL-2 inhibitors","route":"/technologies/bcl2-inhibitors/"},{"id":"bh3-profiling","kind":"technology","name":"BH3 profiling (functional apoptosis testing)","route":"/technologies/bh3-profiling/"},{"id":"senescence-targeting","kind":"technology","name":"Senolytics and senescence-directed therapy","route":"/technologies/senescence-targeting/"}],"drug":[{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"basal-cell-carcinoma-signalling","kind":"pathway","name":"Basal cell carcinoma (KEGG map)","route":"/pathways/basal-cell-carcinoma-signalling/"},{"id":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"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":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"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":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"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/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"idea":[{"id":"lymphoma-ev-genetic-subtype-directed-first-line","kind":"idea","name":"Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain","route":"/ideas/lymphoma-ev-genetic-subtype-directed-first-line/"},{"id":"idea-btk-degrader-frontline","kind":"idea","name":"BTK degraders to pre-empt resistance in frontline CLL","route":"/ideas/idea-btk-degrader-frontline/"},{"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/"},{"id":"idea-sclc-subtype-directed","kind":"idea","name":"Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)","route":"/ideas/idea-sclc-subtype-directed/"}],"trial":[{"id":"amplify","kind":"trial","name":"AMPLIFY","route":"/trials/amplify/"},{"id":"captivate","kind":"trial","name":"CAPTIVATE","route":"/trials/captivate/"},{"id":"celestial-tncll","kind":"trial","name":"CELESTIAL-TNCLL","route":"/trials/celestial-tncll/"},{"id":"cll13-gaia","kind":"trial","name":"CLL13 / GAIA","route":"/trials/cll13-gaia/"},{"id":"cll14","kind":"trial","name":"CLL14","route":"/trials/cll14/"},{"id":"glow","kind":"trial","name":"GLOW","route":"/trials/glow/"},{"id":"viale-a","kind":"trial","name":"VIALE-A","route":"/trials/viale-a/"}],"pairing":[{"id":"btki-plus-venetoclax-fixed-duration","kind":"pairing","name":"BTK inhibitor + venetoclax, fixed duration","route":"/pairings/btki-plus-venetoclax-fixed-duration/"},{"id":"venetoclax-plus-obinutuzumab","kind":"pairing","name":"Venetoclax + obinutuzumab (12 months)","route":"/pairings/venetoclax-plus-obinutuzumab/"}],"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":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/"},{"id":"lymphoma-bio-cell-of-origin-in-practice","kind":"term","name":"Cell of origin in practice: Hans against expression profiling, and what it changes","route":"/terms/lymphoma-bio-cell-of-origin-in-practice/"},{"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":"lymphoma-bio-lymphgen","kind":"term","name":"LymphGen and the genetic clusters of large B-cell lymphoma","route":"/terms/lymphoma-bio-lymphgen/"},{"id":"cyclin-d1-t11-14","kind":"term","name":"t(11;14), cyclin D1 and SOX11","route":"/terms/cyclin-d1-t11-14/"},{"id":"lymphoma-bio-germinal-centre","kind":"term","name":"The germinal centre: why lymphoma starts where antibodies are made","route":"/terms/lymphoma-bio-germinal-centre/"}],"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/"},{"id":"ezh2-y646-mutation","kind":"biomarker","name":"EZH2 gain-of-function mutation (Tyr646, originally Tyr641)","route":"/biomarkers/ezh2-y646-mutation/"}],"paper":[{"id":"paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","kind":"paper","name":"A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications","route":"/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/"},{"id":"paper-amplify-acalabrutinib-venetoclax-nejm-2025","kind":"paper","name":"AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients","route":"/key-papers/paper-amplify-acalabrutinib-venetoclax-nejm-2025/"},{"id":"paper-cll14-venetoclax-obinutuzumab-nejm-2019","kind":"paper","name":"CLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patients","route":"/key-papers/paper-cll14-venetoclax-obinutuzumab-nejm-2019/"},{"id":"paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","kind":"paper","name":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray","route":"/key-papers/paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004/"},{"id":"paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","kind":"paper","name":"Genetics and pathogenesis of diffuse large B-cell lymphoma","route":"/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/"},{"id":"paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018","kind":"paper","name":"Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes","route":"/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/"},{"id":"paper-murano-venetoclax-rituximab-nejm-2018","kind":"paper","name":"MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL","route":"/key-papers/paper-murano-venetoclax-rituximab-nejm-2018/"},{"id":"paper-rosenwald-molecular-profiling-dlbcl-nejm-2002","kind":"paper","name":"The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma","route":"/key-papers/paper-rosenwald-molecular-profiling-dlbcl-nejm-2002/"},{"id":"paper-viale-a-venetoclax-azacitidine-nejm-2020","kind":"paper","name":"VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy","route":"/key-papers/paper-viale-a-venetoclax-azacitidine-nejm-2020/"}],"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":"andrew-wei","kind":"person","name":"Andrew H. Wei","route":"/people/andrew-wei/"},{"id":"anthony-letai","kind":"person","name":"Anthony Letai","route":"/people/anthony-letai/"},{"id":"barbara-eichhorst","kind":"person","name":"Barbara Eichhorst","route":"/people/barbara-eichhorst/"},{"id":"constantine-tam","kind":"person","name":"Constantine S. Tam","route":"/people/constantine-tam/"},{"id":"courtney-dinardo","kind":"person","name":"Courtney D. DiNardo","route":"/people/courtney-dinardo/"},{"id":"john-seymour","kind":"person","name":"John F. Seymour","route":"/people/john-seymour/"},{"id":"kirsten-fischer","kind":"person","name":"Kirsten Fischer","route":"/people/kirsten-fischer/"},{"id":"michael-hallek","kind":"person","name":"Michael Hallek","route":"/people/michael-hallek/"},{"id":"michael-wang","kind":"person","name":"Michael L. Wang","route":"/people/michael-wang/"},{"id":"peter-hillmen","kind":"person","name":"Peter Hillmen","route":"/people/peter-hillmen/"},{"id":"william-wierda","kind":"person","name":"William G. Wierda","route":"/people/william-wierda/"}],"institution":[{"id":"osu-james","kind":"institution","name":"The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute","route":"/institutions/osu-james/"},{"id":"wehi","kind":"institution","name":"Walter and Eliza Hall Institute of Medical Research","route":"/institutions/wehi/"}],"company":[{"id":"ascentage-pharma","kind":"company","name":"Ascentage Pharma","route":"/companies/ascentage-pharma/"}],"target":[{"id":"bax","kind":"target","name":"BAX","route":"/targets/bax/"},{"id":"bim","kind":"target","name":"BIM (BCL2L11)","route":"/targets/bim/"},{"id":"ikzf3","kind":"target","name":"IKZF3 (Aiolos)","route":"/targets/ikzf3/"}]}}