Bcl-2: Difference between revisions

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'''Bcl-2''', encoded in humans by the '''''BCL2''''' [[gene]], is the founding member of the [[apoptosis regulator proteins, Bcl-2 family|Bcl-2 family]] of [[regulator protein]]s. BCL2 blocks programmed cell death ([[apoptosis]]) <ref>{{Citecite journal |last vauthors = Hockenbery |first=D., |last2=Nuñez |first2=G., |last3=Milliman |first3=C., |last4=Schreiber |first4=R.RD, D. |last5=Korsmeyer |first5=S. J.SJ |date=1990-11-22 |title = Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death |url=https://pubmed.ncbi.nlm.nih.gov/2250705/ |journal = Nature | volume = 348 | issue = 6299 | pages = 334–336 | date = November 1990 | pmid = 2250705 | doi = 10.1038/348334a0 |issn=0028-0836 |pmidbibcode =2250705 1990Natur.348..334H }}</ref> while other BCL2 family membermembers can either inhibit or induce it.<ref name="pmid6093263">{{cite journal | vauthors = Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM | title = Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation | journal = Science | volume = 226 | issue = 4678 | pages = 1097–91097–1099 | date = NovNovember 1984 | pmid = 6093263 | doi = 10.1126/science.6093263 | bibcode = 1984Sci...226.1097T }}</ref><ref name="pmid2875799">{{cite journal | vauthors = Cleary ML, Smith SD, Sklar J | s2cid = 31493780 | title = Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation | journal = Cell | volume = 47 | issue = 1 | pages = 19–28 | date = OctOctober 1986 | pmid = 2875799 | doi = 10.1016/0092-8674(86)90362-4 | s2cid = 31493780 }}</ref> It was the first apoptosis regulator identified in any organism.<ref>{{cite journal |vauthors=Kelly GL, Strasser A |title=Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy |year=2020 |journal=Annual Review of Cancer Biology |volume=4 |pages=299–313 |doi=10.1146/annurev-cancerbio-030419-033510 |doi-access=free|hdl=11343/252362 |hdl-access=free }}</ref>

The two [[isoforms]] of Bcl-2, Isoform 1, and Isoform 2, exhibit a similar fold. However, results in the ability of these isoforms to bind to the [[Bcl-2-associated death promoter|BAD]] and [[Bcl-2 homologous antagonist killer|BAK]] proteins, as well as in the structural topology and [[electrostatic potential]] of the binding groove, suggest differences in antiapoptotic activity for the two [[Protein isoform|isoforms]].<ref name="Human Bcl2 1G5M">{{PDB|1G5M}}; {{cite journal | vauthors = Petros AM, Medek A, Nettesheim DG, Kim DH, Yoon HS, Swift K, Matayoshi ED, Oltersdorf T, Fesik SW | title = Solution structure of the antiapoptotic protein bcl-2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages = 3012–73012–3017 | date = March 2001 | pmid = 11248023 | pmc = 30598 | doi = 10.1073/pnas.041619798 | pmcdoi-access = 30598free | bibcode = 2001PNAS...98.3012P | doi-access = free }}</ref>

== Function ==

BCL-2 is localized to the outer membrane of [[Mitochondrion|mitochondria]], where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. The pro-apoptotic proteins in the BCL-2 family, including [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|Bak]], normally act on the mitochondrial membrane to promote permeabilization and release of [[cytochrome c]] and [[Reactive oxygen species|ROS]], that are important signals in the apoptosis cascade. These pro-apoptotic proteins are in turn activated by BH3-only proteins, and are inhibited by the function of BCL-2 and its relative [[Bcl-xL|BCL-Xl]].<ref>{{cite journal |pmid=23378584 |vauthors doi=10.1101/cshperspect.a008722 |Hardwick volume=5JM, |Soane issue=2L | title = Multiple functions of BCL-2 family proteins | pmcjournal =3552500 Cold Spring Harbor Perspectives in Biology | yearvolume =2013 5 | journalissue =Cold Spring2 Harb| Perspectpages Biol= a008722 | vauthorsdate =Hardwick JM,February Soane2013 L| pmid = 23378584 | pagespmc = 3552500 | doi = 10.1101/cshperspect.a008722 }}</ref>

There are additional non-canonical roles of BCL-2 that are being explored. BCL-2 is known to regulate mitochondrial dynamics, and is involved in the regulation of mitochondrial fusion and fission. Additionally, in pancreatic beta-cells, BCL-2 and BCL-Xl are known to be involved in controlling metabolic activity and insulin secretion, with inhibition of BCL-2/Xl showing increasing metabolic activity,<ref>{{cite journal |pmid= 22933114vauthors |doi= 10.2337/db11-1464Luciani |volume=62DS, |issue=1White SA, Widenmaier SB, Saran VV, Taghizadeh F, Hu X, Allard MF, Johnson JD | title = Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ßβ-cells |pmc journal = 3526034Diabetes |year volume =2013 62 |journal issue = Diabetes1 |vauthors= Lucianipages DS,= White170–182 SA,| Widenmaierdate SB,= SaranJanuary VV,2013 Taghizadeh| F,pmid Hu= X,22933114 Allard| MF,pmc Johnson= JD3526034 |pages doi = 170–18210.2337/db11-1464 }}</ref> but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.<ref>{{cite journal |pmid= 27070098vauthors |doi= 10.1210/en.2015Aharoni-1964Simon |volume=157M, |issue=6Shumiatcher R, Yeung A, Shih AZ, Dolinsky VW, Doucette CA, Luciani DS | title = Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ßβ-Cells |year=2016 |journal = Endocrinology |vauthors volume = Aharoni-Simon157 M,| Shumiatcherissue R,= Yeung6 A,| Shihpages AZ,= Dolinsky2270–2281 VW,| Doucettedate CA,= LucianiJune DS2016 |pages pmid = 2270–228127070098 | doi = 10.1210/en.2015-1964 | doi-access = free }}</ref>

Damage to the Bcl-2 gene has been identified as a cause of a number of [[cancer]]s, including [[melanoma]], [[breast cancer|breast]], [[prostate cancer|prostate]], [[chronic lymphocytic leukemia]], and [[lung cancer]], and a possible cause of [[schizophrenia]] and [[autoimmunity]]. It is also a cause of resistance to cancer treatments.<ref name = pmid30544835>{{cite journal | vauthors = GarciaGarcía-Aranda M, PerezPérez-Ruiz E, Redondo M | title = Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy | journal = International Journal of Molecular Sciences | date = Dec 2018 | volume = 19 | issue = 12 | pages = 3950 | date = December 2018 | pmid = 30544835 | pmc = 6321604 | doi = 10.3390/ijms19123950 | doi-access = free }}</ref>

Cancer can be seen as a disturbance in the [[homeostatic]] balance between cell growth and cell death. Over-expression of anti-apoptotic genes, and under-expression of pro-apoptotic genes, can result in the lack of cell death that is characteristic of cancer. An example can be seen in [[lymphoma]]s. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone does not cause cancer. But simultaneous over-expression of Bcl-2 and the proto-oncogene [[myc]] may produce aggressive [[B-cell]] malignancies including lymphoma.<ref name="pmid17179226">{{cite journal | vauthors = Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ | title = Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA | journal = Blood | volume = 109 | issue = 7 | pages = 3069–753069–3075 | date = AprApril 2007 | pmid = 17179226 | pmc = 1852223 | doi = 10.1182/blood-2006-08-043257 }}</ref> In [[follicular lymphoma]], a [[chromosomal translocation]] commonly occurs between the fourteenth and the eighteenth [[chromosome]]s – t(14;18) – which places the Bcl-2 gene from chromosome 18 next to the [[Immunoglobulin superfamily|immunoglobulin]] heavy chain locus on chromosome 14. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.<ref name="pmid3262202">{{cite journal | vauthors = Vaux DL, Cory S, Adams JM | s2cid = 23593952 | title = Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells | journal = Nature | volume = 335 | issue = 6189 | pages = 440–2440–442 | date = SepSeptember 1988 | pmid = 3262202 | doi = 10.1038/335440a0 | s2cid = 23593952 | bibcode = 1988Natur.335..440V }}</ref> This decreases the propensity of these cells for apoptosis. Bcl-2 expression is frequent in [[small cell lung cancer]], accounting for 76% cases in one study.<ref>{{cite journal |last1 vauthors = Kaiser |first1=U., |last2=Schilli |first2=M., |last3=Haag |first3=U., |last4=Neumann |first4=K., |last5=Kreipe |first5=H., |last6=Kogan |first6=E., |last7=Havemann |first7=K. | title = Expression of bcl-2 — --protein in small cell lung cancer | journal = Lung Cancer |date=August 1996 |volume = 15 | issue = 1 | pages = 31–40 | date = August 1996 | pmid = 8865121 | doi = 10.1016/0169-5002(96)00568-5 |pmid=8865121 }}</ref>

[[Apoptosis]] plays an active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-[[antigens]] via both central and peripheral tolerance. In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.<ref name="pmid17162368">{{cite journal | vauthors = Li A, Ojogho O, Escher A | title = Saving death: apoptosis for intervention in transplantation and autoimmunity | journal = Clinical & Developmental Immunology | volume = 13 | issue = 2–4 | pages = 273–82273–282 | year = 2006 | pmid = 17162368 | pmc = 2270759 | doi = 10.1080/17402520600834704 }}</ref> The autoimmune disease [[Diabetes mellitus type 1|type 1 diabetes]] can be caused by defective apoptosis, which leads to aberrant T cell [[Activation-induced cytidine deaminase|AICD]] and defective peripheral tolerance. Due to the fact that [[dendritic cell]]s are the immune system's most important [[antigen-presenting cell]]s, their activity must be tightly regulated by mechanisms such as apoptosis. Researchers have found that mice containing dendritic cells that are [[BCL2L11|Bim]] -/-, thus unable to induce effective apoptosis, have [[autoimmune disease]]s more so than those that have normal dendritic cells.<ref name="pmid17162368"/> Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.<ref name="pmid17162368"/>

Apoptosis plays an important role in regulating a variety of diseases. For example, schizophrenia is a psychiatric disorder in which an abnormal ratio of pro- and anti-apoptotic factors may contribute towards pathogenesis.<ref name="pmid16226876">{{cite journal | vauthors = Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF | s2cid = 22388783 | title = Apoptotic mechanisms and the synaptic pathology of schizophrenia | journal = Schizophrenia Research | volume = 81 | issue = 1 | pages = 47–63 | date = JanJanuary 2006 | pmid = 16226876 | doi = 10.1016/j.schres.2005.08.014 | s2cid = 22388783 }}</ref> Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of [[Caspase 3|caspase-3]].<ref name="pmid16226876"/>

Antibodies to Bcl-2 can be used with [[immunohistochemistry]] to identify cells containing the antigen. In healthy tissue, these antibodies react with B-cells in the [[mantle zone]], as well as some [[T-cell]]s. However, positive cells increase considerably in [[follicular lymphoma]], as well as many other forms of cancer. In some cases, the presence or absence of Bcl-2 staining in [[biopsy|biopsies]] may be significant for the patient's [[prognosis]] or likelihood of [[relapse]].<ref name=Leong>{{cite book| last1 = Leong | first1veditors = AnthonyChetty S-YR, |Cooper last2K, =Gown CooperAM | first2 year= Kumarason2016 | last3chapter = Leong |Section first31 =- FAntibodies: Joel WBcl-M2 |year=2003|title=Manual of Diagnostic Cytology |edition=22nd |publisher=Greenwich Medical Media, Ltd.|pages=XX23-24 | doi = 10.1017/9781139939508.013 |isbn=978-1-84110139-10093950-28 }}</ref>

Human [[lymphoma]] [[cell (biology)|cell]] proliferation (with t(14;18) translocation) could be inhibited by [[antisense RNA]] targeted at the start [[codon]] region of Bcl-2 [[mRNA]]. ''[[In vitro]]'' studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.<ref name="pmid12445555">{{cite journal | vauthors = Dias N, Stein CA | title = Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides | journal = European Journal of Pharmaceutics and Biopharmaceutics | volume = 54 | issue = 3 | pages = 263–9263–269 | date = NovNovember 2002 | pmid = 12445555 | doi = 10.1016/S0939-6411(02)00060-7 }}</ref>

These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.<ref name="pmid15010151">{{cite journal | vauthors = Mavromatis BH, Cheson BD | title = Novel therapies for chronic lymphocytic leukemia | journal = Blood Reviews | volume = 18 | issue = 2 | pages = 137–48137–148 | date = JunJune 2004 | pmid = 15010151 | doi = 10.1016/S0268-960X(03)00039-0 }}</ref> As of 2016, the drug had not been approved and its developer was out of business.<ref>{{Cite web|title = Genasense (oblimersen sodium) FDA Approval Status -| work = Drugs.com|url = https://www.drugs.com/history/genasense.html|website = www.drugs.com|access-date = 2016-02-11}}</ref>

In the mid-2000s, [[Abbott Laboratories]] developed a novel inhibitor of Bcl-2, [[Bcl-xL]] and Bcl-w, known as [[ABT-737]]. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI) that target these Bcl-2 family proteins, but not A1 or [[MCL1|Mcl-1]]. ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. ''In vitro'' studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.<ref>{{cite journal |last1 vauthors = Vogler |first1=M., |last2=Dinsdale |first2=D., |last3=Dyer |first3=M.MJ, J.Cohen S.GM |last4=Cohen |first4title =G. M. |title=Bcl-2 inhibitors: small molecules with a big impact on cancer therapy | journal = Cell Death &and Differentiation |date=March 2009 |volume = 16 | issue = 3 | pages = 360–367 | date = March 2009 | pmid = 18806758 | doi = 10.1038/cdd.2008.137 |pmid hdl-access =18806758 free | s2cid = 24538054 | doi-access = free | hdl = 2381/4756 |hdl-access=free }}</ref> ABT-737 does not directly induce apoptosis; it enhances the effects of apoptotic signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines.{{Citation needed|reason=Claim that ABT-737 does not directly induce apoptosis is not supported|date=January 2017}}

In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.<ref>{{cite journal | vauthors = Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH | s2cid = 4335635 | display-authors = 6 | title = An inhibitor of Bcl-2 family proteins induces regression of solid tumours | journal = Nature | volume = 435 | issue = 7042 | pages = 677–81677–681 | date = June 2005 | pmid = 15902208 | doi = 10.1038/nature03579 | s2cid = 4335635 | bibcode = 2005Natur.435..677O }}</ref> In preclinical studies utilizing [[Patient derived tumor xenografts|patient xenografts]], ABT-737 showed efficacy for treating lymphoma and other blood cancers.<ref>{{cite journal | vauthors = Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM | title = Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer | journal = Cancer Research | volume = 68 | issue = 7 | pages = 2321–82321–2328 | date = April 2008 | pmid = 18381439 | pmc = 3159963 | doi = 10.1158/0008-5472.can-07-5031 }}</ref> Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its orally [[Bioavailability|bioavailable]] derivative [[navitoclax]] (ABT-263) has similar activity on [[small cell lung cancer]] (SCLC) cell lines and has entered clinical trials.<ref name="hauck2009">{{cite journal |last1 vauthors = Hauck |first1=P., |last2=Chao |first2=B.BH, H. |last3=Litz |first3=J., |last4=Krystal GW |first4=G. W.title |title= Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737 | journal = Molecular Cancer Therapeutics |date=1 April 2009 |volume = 8 | issue = 4 | pages = 883–892 | date = April 2009 | pmid = 19372561 | doi = 10.1158/1535-7163.MCT-08-1118 |pmid=19372561 |s2cid = 19245418 | doi-access = }}</ref> While clinical responses with navitoclax were promising, mechanistic dose-limiting [[thrombocytopenia]] was observed in patients under treatment due to Bcl-xL inhibition in [[platelet]]s.<ref>{{cite journal | vauthors = Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM | title = Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors | journal = Journal of Clinical Oncology | volume = 29 | issue = 7 | pages = 909–16909–916 | date = March 2011 | pmid = 21282543 | pmc = 4668282 | doi = 10.1200/JCO.2010.31.6208 }}</ref><ref>{{cite journal | vauthors = Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L | title = Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer | journal = Clinical Cancer Research | volume = 18 | issue = 11 | pages = 3163–93163–3169 | date = June 2012 | pmid = 22496272 | pmc = 3715059 | doi = 10.1158/1078-0432.CCR-11-3090 }}</ref><ref>{{cite journal | vauthors = Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H | s2cid = 10685695 | title = Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia | journal = Cancer Chemotherapy and Pharmacology | volume = 74 | issue = 3 | pages = 593–602 | date = September 2014 | pmid = 25053389 | doi = 10.1007/s00280-014-2530-9 | s2cid = 10685695 }}</ref>

Due to dose-limiting thrombocytopenia of navitoclax as a result of Bcl-xL inhibition, [[Abbvie]] successfully developed the highly selective inhibitor [[venetoclax]] (ABT-199), which inhibits Bcl-2, but not Bcl-xL or Bcl-w.<ref>{{cite journal | vauthors = Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, Cortes J, DeAngelo DJ, Debose L, Mu H, Döhner H, Gaidzik VI, Galinsky I, Golfman LS, Haferlach T, Harutyunyan KG, Hu J, Leverson JD, Marcucci G, Müschen M, Newman R, Park E, Ruvolo PP, Ruvolo V, Ryan J, Schindela S, Zweidler-McKay P, Stone RM, Kantarjian H, Andreeff M, Konopleva M, Letai AG | title = Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia | journal = Cancer Discovery | volume = 4 | issue = 3 | pages = 362–75362–375 | date = March 2014 | pmid = 24346116 | pmc = 3975047 | doi = 10.1158/2159-8290.CD-13-0609 }}</ref> Clinical trials studied the effects of venetoclax, a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with [[chronic lymphocytic leukemia]] (CLL).<ref>{{cite news |title=ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia |first=Grace |last=Liao |date=12 August 2011 |url=http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia |publisher=Asian Scientist |access-date=11 February 2016 |url-status=dead |archive-url=https://web.archive.org/web/20120718151431/http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia/ |archive-date=18 July 2012 |df=dmy }}</ref><ref name=":0">{{cite journal | vauthors = Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF | title = Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia | journal = The New England Journal of Medicine | volume = 374 | issue = 4 | pages = 311–22311–322 | date = January 2016 | pmid = 26639348 | doipmc = 10.1056/NEJMoa15132577107002 | pmcdoi = 710700210.1056/NEJMoa1513257 | doi-access = free }}</ref> Good responses have been reported and thrombocytopenia was no longer observed.<ref name=":0" /><ref>{{cite web|url=http://www.stokesentinel.co.uk/Miracle-drug-cured-cancer-Amazing-recovery/story-21080535-detail/story.html|title='Miracle drug cured my cancer!': Amazing three-week recovery of Staffordshire sufferer|work=Stoke Sentinel|access-date=10 May 2014|archive-url=https://web.archive.org/web/20140512200023/http://www.stokesentinel.co.uk/Miracle-drug-cured-cancer-Amazing-recovery/story-21080535-detail/story.html|archive-date=12 May 2014|url-status=dead|df=dmy-all}}</ref> A phase 3 trial started in Dec 2015.<ref name=ASH2015-V>{{cite web|url=http://www.medpagetoday.com/MeetingCoverage/ASHHematology/55056|title=Hard-to-Treat CLL Yields to Investigational Drug| first = Michael | last = Smith |date=7 December 2015 }}</ref>

Venetoclax drug resistance has been noted with the G101V mutation in BCL-2 observed in relapsing patients.<ref>{{cite journal |last1 vauthors = Blombery |first1=PiersP, |last2=Anderson |first2=MaryMA, Ann |last3=Gong |first3=Jia-nanJN, |last4=Thijssen |first4=RachelR, |last5=Birkinshaw |first5=RichardRW, W. |last6=Thompson |first6=EllaER, R. |last7=Teh |first7=CharisCE, E. |last8=Nguyen |first8=TamiaT, |last9=Xu |first9=ZhenZ, |last10=Flensburg |first10=ChristofferC, |last11=Lew |first11=ThomasTE, E. |last12=Majewski |first12=IanIJ, J. |last13=Gray |first13=DanielDH, H.D. |last14=Westerman |first14=DavidDA, A. |last15=Tam |first15=ConstantineCS, S. |last16=Seymour |first16=JohnJF, F. |last17=Czabotar |first17=PeterPE, E. |last18=Huang |first18=DavidDC, C.S. |last19=Roberts AW |first19=Andrew W. |title = Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia | journal = Cancer Discovery |date=1 Marchvolume 2019= |volume=9 | issue = 3 | pages = 342–353 | date = March 2019 | pmid = 30514704 | doi = 10.1158/2159-8290.CD-18-1119 }}</ref> Sonrotoclax shows greater tumor growth inhibition in hematologic tumor models than venetoclax and inhibits venetoclax-resistant BCL-2 variants. Sonrotoclax is under clinical investigation as a monotherapy and in combination with other anticancer agents.<ref>{{cite journal |last1 vauthors = Liu |first1=JiuyangJ, |last2=Li |first2=ShuranS, |last3=Wang |first3=QinQ, |last4=Feng |first4=YingcaiY, |last5=Xing |first5=HaimeiH, |last6=Yang |first6=XuefeiX, |last7=Guo |first7=YingY, |last8=Guo |first8=YunhangY, |last9=Sun |first9=HanziH, |last10=Liu |first10=XiaoxinX, |last11=Yang |first11=ShashaS, |last12=Mei |first12=ZhuZ, |last13=Zhu |first13=YutongY, |last14=Cheng |first14=ZhenzhenZ, |last15=Chen |first15=ShuaishuaiS, |last16=Xu |first16=MinM, |last17=Zhang |first17=WenjingW, |last18=Wan |first18=NanyanN, |last19=Wang |first19=JiaJ, |last20=Ma |first20=YanwenY, |last21=Zhang |first21=ShuoS, |last22=Luan |first22=XudongX, |last23=Xu |first23=AiyingA, |last24=Li |first24=LinL, |last25=Wang |first25=HaitaoH, |last26=Yang |first26=XiaolongX, |last27=Hong |first27=YuanY, |last28=Xue |first28=HaiH, |last29=Yuan |first29=XiX, |last30=Hu |first30=NanN, |last31=Song |first31=XiaominX, |last32=Wang |first32=ZhiweiZ, |last33=Liu |first33=XuesongX, |last34=Wang |first34=LaiL, |last35=Liu Y |first35=Ye |title = Sonrotoclax overcomes BCL2 G101V mutation–inducedmutation-induced venetoclax resistance in preclinical models of hematologic malignancy | journal = Blood |date=2 May 2024 |volume = 143 | issue = 18 | pages = 1825–1836 | date = May 2024 | pmid = 38211332 | pmc = 11076911 | doi = 10.1182/blood.2023019706|pmc=11076911 }}</ref>

* [[BAK1]],<ref name = pmid14980220>{{cite journal | vauthors = Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK | title = Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 | journal = Cell | volume = 116 | issue = 4 | pages = 527–40527–540 | date = FebFebruary 2004 | pmid = 14980220 | doi = 10.1016/s0092-8674(04)00162-x | s2cid = 17808479 | doi-access = free }}</ref><ref name = pmid11728179>{{cite journal | vauthors = Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X, Huang Y, Long YQ, Roller PP, Yang D, Wang S | title = Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 25 | pages = 4313–244313–4324 | date = DecDecember 2001 | pmid = 11728179 | doi = 10.1021/jm010016f }}</ref>

* [[BCAP31]],<ref name = pmid9334338>{{cite journal | vauthors = Ng FW, Nguyen M, Kwan T, Branton PE, Nicholson DW, Cromlish JA, Shore GC | title = p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum | journal = The Journal of Cell Biology | volume = 139 | issue = 2 | pages = 327–38327–338 | date = OctOctober 1997 | pmid = 9334338 | pmc = 2139787 | doi = 10.1083/jcb.139.2.327 }}</ref>

* [[BCL2-like 1 (gene)|BCL2-like 1]],<ref name = pmid14980220/><ref name = pmid12137781>{{cite journal | vauthors = Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M | title = Development of a high-throughput fluorescence polarization assay for Bcl-x(L) | journal = Analytical Biochemistry | volume = 307 | issue = 1 | pages = 70–570–75 | date = AugAugust 2002 | pmid = 12137781 | doi = 10.1016/s0003-2697(02)00028-3 }}</ref>

* [[BCL2L11]],<ref name = pmid15694340/><ref name = pmid9430630>{{cite journal | vauthors = O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC | title = Bim: a novel member of the Bcl-2 family that promotes apoptosis | journal = The EMBO Journal | volume = 17 | issue = 2 | pages = 384–95384–395 | date = JanJanuary 1998 | pmid = 9430630 | pmc = 1170389 | doi = 10.1093/emboj/17.2.384 }}</ref><ref name = pmid9731710>{{cite journal | vauthors = Hsu SY, Lin P, Hsueh AJ | title = BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members | journal = Molecular Endocrinology | volume = 12 | issue = 9 | pages = 1432–401432–1440 | date = SepSeptember 1998 | pmid = 9731710 | doi = 10.1210/mend.12.9.0166 | doi-access = free }}</ref>

* [[BECN1]],<ref name = pmid9765397>{{cite journal | vauthors = Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B | title = Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein | journal = Journal of Virology | volume = 72 | issue = 11 | pages = 8586–968586–8596 | date = NovNovember 1998 | pmid = 9765397 | pmc = 110269 | doi = 10.1128/JVI.72.11.8586-8596.1998 }}</ref>

* [[BH3 interacting domain death agonist|BID]],<ref name = pmid15694340/><ref name = pmid15520201>{{cite journal | vauthors = Real PJ, Cao Y, Wang R, Nikolovska-Coleska Z, Sanz-Ortiz J, Wang S, Fernandez-Luna JL | title = Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2 | journal = Cancer Research | volume = 64 | issue = 21 | pages = 7947–537947–7953 | date = NovNovember 2004 | pmid = 15520201 | doi = 10.1158/0008-5472.CAN-04-0945 | s2cid = 11807428 | doi-access = }}</ref>

* [[BMF (gene)|BMF]],<ref name = pmid11546872>{{cite journal | vauthors = Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A | s2cid = 5638023 | title = Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis | journal = Science | volume = 293 | issue = 5536 | pages = 1829–321829–1832 | date = SepSeptember 2001 | pmid = 11546872 | doi = 10.1126/science.1062257 | s2cid = 5638023 | bibcode = 2001Sci...293.1829P }}</ref>

* [[BNIP2]],<ref name = pmid12901880/><ref name = pmid7954800>{{cite journal | vauthors = Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G | s2cid = 38609845 | title = Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins | journal = Cell | volume = 79 | issue = 2 | pages = 341–51341–351 | date = OctOctober 1994 | pmid = 7954800 | doi = 10.1016/0092-8674(94)90202-X | s2cid = 38609845 }}</ref>

* [[BNIP3]],<ref name = pmid7954800/><ref name = pmid10625696>{{cite journal | vauthors = Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Gietz RD, Greenberg AH | title = BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites | journal = The Journal of Biological Chemistry | volume = 275 | issue = 2 | pages = 1439–481439–1448 | date = JanJanuary 2000 | pmid = 10625696 | doi = 10.1074/jbc.275.2.1439 | doi-access = free }}</ref>

* [[BNIPL]],<ref name = pmid12901880>{{cite journal | vauthors = Qin W, Hu J, Guo M, Xu J, Li J, Yao G, Zhou X, Jiang H, Zhang P, Shen L, Wan D, Gu J | title = BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis | journal = Biochemical and Biophysical Research Communications | volume = 308 | issue = 2 | pages = 379–85379–385 | date = AugAugust 2003 | pmid = 12901880 | doi = 10.1016/s0006-291x(03)01387-1 }}</ref><ref name = pmid9973195>{{cite journal | vauthors = Yasuda M, Han JW, Dionne CA, Boyd JM, Chinnadurai G | title = BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3 | journal = Cancer Research | volume = 59 | issue = 3 | pages = 533–7533–537 | date = FebFebruary 1999 | pmid = 9973195 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9973195 }}</ref>

* [[Bcl-2-associated death promoter|BAD]]<ref name = pmid15694340/><ref name = pmid7834748>{{cite journal | vauthors = Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ | s2cid = 10343291 | title = Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death | journal = Cell | volume = 80 | issue = 2 | pages = 285–91285–291 | date = JanJanuary 1995 | pmid = 7834748 | doi = 10.1016/0092-8674(95)90411-5 | s2cid = 10343291 | doi-access = free }}</ref>

* [[Bcl-2-associated X protein|BAX]],<ref name = pmid14980220/><ref name = pmid10620799/><ref name = pmid15231068>{{cite journal | vauthors = Hoetelmans RW | title = Nuclear partners of Bcl-2: Bax and PML | journal = DNA and Cell Biology | volume = 23 | issue = 6 | pages = 351–4351–354 | date = JunJune 2004 | pmid = 15231068 | doi = 10.1089/104454904323145236 }}</ref><ref name = pmid8358790>{{cite journal | vauthors = Oltvai ZN, Milliman CL, Korsmeyer SJ | s2cid = 31151334 | title = Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death | journal = Cell | volume = 74 | issue = 4 | pages = 609–19609–619 | date = AugAugust 1993 | pmid = 8358790 | doi = 10.1016/0092-8674(93)90509-O | s2cid = 31151334 }}</ref>

* [[Bcl-2-interacting killer|BIK]],<ref name = pmid15694340>{{cite journal | vauthors = Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC | title = Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function | journal = Molecular Cell | volume = 17 | issue = 3 | pages = 393–403 | date = FebFebruary 2005 | pmid = 15694340 | doi = 10.1016/j.molcel.2004.12.030 | doi-access = free }}</ref><ref name = pmid12853473>{{cite journal | vauthors = Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT | title = Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway | journal = The EMBO Journal | volume = 22 | issue = 14 | pages = 3580–903580–3590 | date = JulJuly 2003 | pmid = 12853473 | pmc = 165613 | doi = 10.1093/emboj/cdg343 }}</ref>

* [[C-Raf]],<ref name = pmid8929532>{{cite journal | vauthors = Wang HG, Rapp UR, Reed JC | title = Bcl-2 targets the protein kinase Raf-1 to mitochondria | journal = Cell | volume = 87 | issue = 4 | pages = 629–38629–638 | date = NovNovember 1996 | pmid = 8929532 | doi = 10.1016/s0092-8674(00)81383-5 | s2cid = 16559750 | doi-access = free }}</ref>

* [[CAPN2]],<ref name = pmid12000759>{{cite journal | vauthors = Gil-Parrado S, Fernández-Montalván A, Assfalg-Machleidt I, Popp O, Bestvater F, Holloschi A, Knoch TA, Auerswald EA, Welsh K, Reed JC, Fritz H, Fuentes-Prior P, Spiess E, Salvesen GS, Machleidt W | title = Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members | journal = The Journal of Biological Chemistry | volume = 277 | issue = 30 | pages = 27217–2627217–27226 | date = JulJuly 2002 | pmid = 12000759 | doi = 10.1074/jbc.M202945200 | doi-access = free }}</ref>

* [[Caspase 8|CASP8]],<ref name = pmid11406564>{{cite journal | vauthors = Poulaki V, Mitsiades N, Romero ME, Tsokos M | title = Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2 | journal = Cancer Research | volume = 61 | issue = 12 | pages = 4864–724864–4872 | date = JunJune 2001 | pmid = 11406564 }}</ref><ref name = pmid11832478>{{cite journal | vauthors = Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES | title = Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 13430–713430–13437 | date = AprApril 2002 | pmid = 11832478 | doi = 10.1074/jbc.M108029200 | doi-access = free }}</ref>

* [[Cdk1]],<ref name = pmid11774038>{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Basu A, Haldar S, Reed JC | title = Microtubule-targeting drugs induce bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 6 | pages = 550–9550–559 | year = 2001 | pmid = 11774038 | pmc = 1506558 | doi = 10.1038/sj.neo.7900213 | year = 2001 }}</ref><ref name = pmid11326318>{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Haldar S, Reed JC | title = Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 1 | pages = 70–970–79 | year = 2001 | pmid = 11326318 | pmc = 1505024 | doi = 10.1038/sj.neo.7900131 | year = 2001 }}</ref>

* [[HRK (gene)|HRK]],<ref name = pmid15694340/><ref name = pmid9130713>{{cite journal | vauthors = Inohara N, Ding L, Chen S, Núñez G | title = harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L) | journal = The EMBO Journal | volume = 16 | issue = 7 | pages = 1686–941686–1694 | date = AprApril 1997 | pmid = 9130713 | pmc = 1169772 | doi = 10.1093/emboj/16.7.1686 }}</ref>

* [[IRS1]],<ref name = pmid10679027>{{cite journal | vauthors = Ueno H, Kondo E, Yamamoto-Honda R, Tobe K, Nakamoto T, Sasaki K, Mitani K, Furusaka A, Tanaka T, Tsujimoto Y, Kadowaki T, Hirai H | title = Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function | journal = Molecular Biology of the Cell | volume = 11 | issue = 2 | pages = 735–46735–746 | date = FebFebruary 2000 | pmid = 10679027 | pmc = 14806 | doi = 10.1091/mbc.11.2.735 }}</ref>

* [[Myc]],<ref name = pmid15210690>{{cite journal | vauthors = Jin Z, Gao F, Flagg T, Deng X | title = Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages = 40209–1940209–40219 | date = SepSeptember 2004 | pmid = 15210690 | doi = 10.1074/jbc.M404056200 | doi-access = free }}</ref>

* [[Noxa]],<ref name = pmid15694340/><ref name = pmid10807576>{{cite journal | vauthors = Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N | title = Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis | journal = Science | volume = 288 | issue = 5468 | pages = 1053–81053–1058 | date = May 2000 | pmid = 10807576 | doi = 10.1126/science.288.5468.1053 | bibcode = 2000Sci...288.1053O }}</ref>

* [[PPP2CA]],<ref name = pmid9852076>{{cite journal | vauthors = Deng X, Ito T, Carr B, Mumby M, May WS | title = Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A | journal = The Journal of Biological Chemistry | volume = 273 | issue = 51 | pages = 34157–6334157–34163 | date = DecDecember 1998 | pmid = 9852076 | doi = 10.1074/jbc.273.51.34157 | doi-access = free }}</ref>

* [[PSEN1]],<ref name = pmid10521466>{{cite journal | vauthors = Alberici A, Moratto D, Benussi L, Gasparini L, Ghidoni R, Gatta LB, Finazzi D, Frisoni GB, Trabucchi M, Growdon JH, Nitsch RM, Binetti G | title = Presenilin 1 protein directly interacts with Bcl-2 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 43 | pages = 30764–930764–30769 | date = OctOctober 1999 | pmid = 10521466 | doi = 10.1074/jbc.274.43.30764 | doi-access = free }}</ref>

* [[RAD9A]],<ref name = pmid10620799>{{cite journal | vauthors = Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG | s2cid = 52847351 | title = Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis | journal = Nature Cell Biology | volume = 2 | issue = 1 | pages = 1–6 | date = JanJanuary 2000 | pmid = 10620799 | doi = 10.1038/71316 | s2cid = 52847351 }}</ref>

* [[RRAS]],<ref name = pmid8232588>{{cite journal | vauthors = Fernandez-Sarabia MJ, Bischoff JR | s2cid = 4312803 | title = Bcl-2 associates with the ras-related protein R-ras p23 | journal = Nature | volume = 366 | issue = 6452 | pages = 274–5274–275 | date = NovNovember 1993 | pmid = 8232588 | doi = 10.1038/366274a0 | s2cid = 4312803 | bibcode = 1993Natur.366..274F }}</ref>

* [[Reticulon 4|RTN4]],<ref name = pmid11126360>{{cite journal | vauthors = Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y | title = A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity | journal = Oncogene | volume = 19 | issue = 50 | pages = 5736–465736–5746 | date = NovNovember 2000 | pmid = 11126360 | doi = 10.1038/sj.onc.1203948 | doi-access = free }}</ref>

* [[SMN1]],<ref name = pmid9389483>{{cite journal | vauthors = Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y | s2cid = 1936633 | title = Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy | journal = Nature | volume = 390 | issue = 6658 | pages = 413–7413–417 | date = NovNovember 1997 | pmid = 9389483 | doi = 10.1038/37144 | s2cid = 1936633 | bibcode = 1997Natur.390..413I }}</ref>

* [[SOD1]],<ref name = pmid15233914>{{cite journal | vauthors = Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH | s2cid = 18141051 | title = Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria | journal = Neuron | volume = 43 | issue = 1 | pages = 19–30 | date = JulJuly 2004 | pmid = 15233914 | doi = 10.1016/j.neuron.2004.06.021 | s2cid = 18141051 | doi-access = free }}</ref> and

* [[TP53BP2]].<ref name = pmid8668206>{{cite journal | vauthors = Naumovski L, Cleary ML | title = The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M | journal = Molecular and Cellular Biology | volume = 16 | issue = 7 | pages = 3884–923884–3892 | date = JulJuly 1996 | pmid = 8668206 | pmc = 231385 | doi = 10.1128/MCB.16.7.3884 }}</ref>