The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

1st Department of Internal Medicine Department of Hematology Charles University General Hospital Prague 12808 Prague Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague 12853 Prague Czech Republic

Zobrazit více v PubMed

Kerr J.F., Wyllie A.H., Currie A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer. 1972;26:239–257. doi: 10.1038/bjc.1972.33. PubMed DOI PMC

Dixon S.J. Ferroptosis: Bug or feature? Immunol. Rev. 2017;277:150–157. doi: 10.1111/imr.12533. PubMed DOI

Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer. 2002;2:420–430. doi: 10.1038/nrc821. PubMed DOI

Trapani J.A., Smyth M.J. Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol. 2002;2:735–747. doi: 10.1038/nri911. PubMed DOI

Voskoboinik I., Whisstock J.C., Trapani J.A. Perforin and granzymes: Function, dysfunction and human pathology. Nat. Rev. Immunol. 2015;15:388–400. doi: 10.1038/nri3839. PubMed DOI

Sutton V.R., Davis J.E., Cancilla M., Johnstone R.W., Ruefli A.A., Sedelies K., Browne K.A., Trapani J.A. Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J. Exp. Med. 2000;192:1403–1414. doi: 10.1084/jem.192.10.1403. PubMed DOI PMC

Beresford P.J., Xia Z., Greenberg A.H., Lieberman J. Granzyme A loading induces rapid cytolysis and a novel form of DNA damage independently of caspase activation. Immunity. 1999;10:585–594. doi: 10.1016/S1074-7613(00)80058-8. PubMed DOI

Huppertz B., Frank H.G., Kaufmann P. The apoptosis cascade--morphological and immunohistochemical methods for its visualization. Anat. Embryol. (Berl) 1999;200:1–18. doi: 10.1007/s004290050254. PubMed DOI

Hegde R., Srinivasula S.M., Zhang Z., Wassell R., Mukattash R., Cilenti L., DuBois G., Lazebnik Y., Zervos A.S., Fernandes-Alnemri T., et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 2002;277:432–438. doi: 10.1074/jbc.M109721200. PubMed DOI

Yang Q.H., Church-Hajduk R., Ren J., Newton M.L., Du C. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 2003;17:1487–1496. doi: 10.1101/gad.1097903. PubMed DOI PMC

Liu Z., Sun C., Olejniczak E.T., Meadows R.P., Betz S.F., Oost T., Herrmann J., Wu J.C., Fesik S.W. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature. 2000;408:1004–1008. doi: 10.1038/35050006. PubMed DOI

Singh R., Letai A., Sarosiek K. Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 2019;20:175–193. doi: 10.1038/s41580-018-0089-8. PubMed DOI PMC

Warren C.F.A., Wong-Brown M.W., Bowden N.A. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis. 2019;10:177. doi: 10.1038/s41419-019-1407-6. PubMed DOI PMC

Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. PubMed DOI

Kim J.H., Bae J. MCL-1ES induces MCL-1L-dependent BAX- and BAK-independent mitochondrial apoptosis. PLoS ONE. 2013;8:e79626. doi: 10.1371/journal.pone.0079626. PubMed DOI PMC

Nechushtan A., Smith C.L., Lamensdorf I., Yoon S.H., Youle R.J. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J. Cell Biol. 2001;153:1265–1276. doi: 10.1083/jcb.153.6.1265. PubMed DOI PMC

Ke F., Bouillet P., Kaufmann T., Strasser A., Kerr J., Voss A.K. Consequences of the combined loss of BOK and BAK or BOK and BAX. Cell Death Dis. 2013;4:e650. doi: 10.1038/cddis.2013.176. PubMed DOI PMC

Certo M., Del Gaizo Moore V., Nishino M., Wei G., Korsmeyer S., Armstrong S.A., Letai A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9:351–365. doi: 10.1016/j.ccr.2006.03.027. PubMed DOI

Merino D., Kelly G.L., Lessene G., Wei A.H., Roberts A.W., Strasser A. BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines. Cancer Cell. 2018;34:879–891. doi: 10.1016/j.ccell.2018.11.004. PubMed DOI

Nogai H., Dorken B., Lenz G. Pathogenesis of non-Hodgkin’s lymphoma. J. Clin. Oncol. 2011;29:1803–1811. doi: 10.1200/JCO.2010.33.3252. PubMed DOI

Schatz D.G., Oettinger M.A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989;59:1035–1048. doi: 10.1016/0092-8674(89)90760-5. PubMed DOI

LeBien T.W., Tedder T.F. B lymphocytes: How they develop and function. Blood. 2008;112:1570–1580. doi: 10.1182/blood-2008-02-078071. PubMed DOI PMC

Muramatsu M., Kinoshita K., Fagarasan S., Yamada S., Shinkai Y., Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102:553–563. doi: 10.1016/S0092-8674(00)00078-7. PubMed DOI

Swerdlow S.H., Campo E., Pileri S.A., Harris N.L., Stein H., Siebert R., Advani R., Ghielmini M., Salles G.A., Zelenetz A.D., et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. doi: 10.1182/blood-2016-01-643569. PubMed DOI PMC

The Non-Hodgkin’s Lymphoma Classification Project A Clinical Evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin’s Lymphoma. Blood. 1997;89:3909–3918. doi: 10.1182/blood.V89.11.3909. PubMed DOI

Alizadeh A.A., Eisen M.B., Davis R.E., Ma C., Lossos I.S., Rosenwald A., Boldrick J.C., Sabet H., Tran T., Yu X., et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511. doi: 10.1038/35000501. PubMed DOI

Vitolo U., Trneny M., Belada D., Burke J.M., Carella A.M., Chua N., Abrisqueta P., Demeter J., Flinn I., Hong X., et al. Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2017 doi: 10.1200/JCO.2017.73.3402. PubMed DOI

Lenz G., Wright G., Dave S.S., Xiao W., Powell J., Zhao H., Xu W., Tan B., Goldschmidt N., Iqbal J., et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 2008;359:2313–2323. doi: 10.1056/NEJMoa0802885. PubMed DOI PMC

Tsujimoto Y., Finger L.R., Yunis J., Nowell P.C., Croce C.M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984;226:1097–1099. doi: 10.1126/science.6093263. PubMed DOI

Scott D.W., Mottok A., Ennishi D., Wright G.W., Farinha P., Ben-Neriah S., Kridel R., Barry G.S., Hother C., Abrisqueta P., et al. Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. J. Clin. Oncol. 2015;33:2848–2856. doi: 10.1200/JCO.2014.60.2383. PubMed DOI PMC

Hu S., Xu-Monette Z.Y., Tzankov A., Green T., Wu L., Balasubramanyam A., Liu W.M., Visco C., Li Y., Miranda R.N., et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: A report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121:4021–4031. doi: 10.1182/blood-2012-10-460063. PubMed DOI PMC

Sehn L.H., Oestergaard M.Z., Trněný M., Bosi A., Egyed M., Illes A., Nakamae H., Opat S., Topp M., Zaja F., et al. Prognostic impact of bcl2 and myc expression and translocation in untreated dlbcl: Results from the phase iii goya study. Hematol. Oncol. 2017;35:131–133. doi: 10.1002/hon.2437_121. DOI

Bolen C.R., Klanova M., Trneny M., Sehn L.H., He J., Tong J., Paulson J.N., Kim E., Vitolo U., Di Rocco A., et al. Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: Data from the phase III GOYA study. Haematologica. 2019 doi: 10.3324/haematol.2019.227892. PubMed DOI PMC

Iqbal J., Neppalli V.T., Wright G., Dave B.J., Horsman D.E., Rosenwald A., Lynch J., Hans C.P., Weisenburger D.D., Greiner T.C., et al. BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J. Clin. Oncol. 2006;24:961–968. doi: 10.1200/JCO.2005.03.4264. PubMed DOI

Leich E., Salaverria I., Bea S., Zettl A., Wright G., Moreno V., Gascoyne R.D., Chan W.C., Braziel R.M., Rimsza L.M., et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009;114:826–834. doi: 10.1182/blood-2009-01-198580. PubMed DOI PMC

Bende R.J., Smit L.A., van Noesel C.J. Molecular pathways in follicular lymphoma. Leukemia. 2007;21:18–29. doi: 10.1038/sj.leu.2404426. PubMed DOI

Guo Y., Karube K., Kawano R., Suzumiya J., Takeshita M., Kikuchi M., Huang G.-S., Li Q., Ohshima K. Bcl2-negative follicular lymphomas frequently have Bcl6 translocation and/or Bcl6 or p53 expression. Pathol. Int. 2007;57:148–152. doi: 10.1111/j.1440-1827.2006.02072.x. PubMed DOI

Davids M.S., Roberts A.W., Seymour J.F., Pagel J.M., Kahl B.S., Wierda W.G., Puvvada S., Kipps T.J., Anderson M.A., Salem A.H., et al. Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J. Clin. Oncol. 2017;35:826–833. doi: 10.1200/JCO.2016.70.4320. PubMed DOI PMC

Tagawa H., Karnan S., Suzuki R., Matsuo K., Zhang X., Ota A., Morishima Y., Nakamura S., Seto M. Genome-wide array-based CGH for mantle cell lymphoma: Identification of homozygous deletions of the proapoptotic gene BIM. Oncogene. 2005;24:1348–1358. doi: 10.1038/sj.onc.1208300. PubMed DOI

Masque-Soler N., Szczepanowski M., Kohler C.W., Aukema S.M., Nagel I., Richter J., Siebert R., Spang R., Burkhardt B., Klapper W. Clinical and pathological features of Burkitt lymphoma showing expression of BCL2--an analysis including gene expression in formalin-fixed paraffin-embedded tissue. Br. J. Haematol. 2015;171:501–508. doi: 10.1111/bjh.13624. PubMed DOI

Majid A., Tsoulakis O., Walewska R., Gesk S., Siebert R., Kennedy D.B., Dyer M.J. BCL2 expression in chronic lymphocytic leukemia: Lack of association with the BCL2 938A>C promoter single nucleotide polymorphism. Blood. 2008;111:874–877. doi: 10.1182/blood-2007-07-098681. PubMed DOI

Calin G.A., Dumitru C.D., Shimizu M., Bichi R., Zupo S., Noch E., Aldler H., Rattan S., Keating M., Rai K., et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA. 2002;99:15524–15529. doi: 10.1073/pnas.242606799. PubMed DOI PMC

Hanada M., Delia D., Aiello A., Stadtmauer E., Reed J.C. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993;82:1820–1828. doi: 10.1182/blood.V82.6.1820.1820. PubMed DOI

Lai R., Arber D.A., Chang K.L., Wilson C.S., Weiss L.M. Frequency of bcl-2 expression in non-Hodgkin’s lymphoma: A study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Mod. Pathol. 1998;11:864–869. PubMed

Bakhshi A., Jensen J.P., Goldman P., Wright J.J., McBride O.W., Epstein A.L., Korsmeyer S.J. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. 1985;41:899–906. doi: 10.1016/S0092-8674(85)80070-2. PubMed DOI

Rosenwald A., Wright G., Chan W.C., Connors J.M., Campo E., Fisher R.I., Gascoyne R.D., Muller-Hermelink H.K., Smeland E.B., Giltnane J.M., et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002;346:1937–1947. doi: 10.1056/NEJMoa012914. PubMed DOI

Schuetz J.M., Johnson N.A., Morin R.D., Scott D.W., Tan K., Ben-Nierah S., Boyle M., Slack G.W., Marra M.A., Connors J.M., et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia. 2012;26:1383–1390. doi: 10.1038/leu.2011.378. PubMed DOI

Stilgenbauer S., Nickolenko J., Wilhelm J., Wolf S., Weitz S., Dohner K., Boehm T., Dohner H., Lichter P. Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene. 1998;16:1891–1897. doi: 10.1038/sj.onc.1201764. PubMed DOI

Cimmino A., Calin G.A., Fabbri M., Iorio M.V., Ferracin M., Shimizu M., Wojcik S.E., Aqeilan R.I., Zupo S., Dono M., et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl. Acad. Sci. USA. 2005;102:13944–13949. doi: 10.1073/pnas.0506654102. PubMed DOI PMC

Robertson L.E., Plunkett W., McConnell K., Keating M.J., McDonnell T.J. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 1996;10:456–459. PubMed

Dohner H., Stilgenbauer S., Benner A., Leupolt E., Krober A., Bullinger L., Dohner K., Bentz M., Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. 2000;343:1910–1916. doi: 10.1056/NEJM200012283432602. PubMed DOI

Adams C.M., Mitra R., Gong J.Z., Eischen C.M. Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW. Clin. Cancer Res. 2017;23:7119–7129. doi: 10.1158/1078-0432.CCR-17-1144. PubMed DOI PMC

Zhou P., Levy N.B., Xie H., Qian L., Lee C.Y., Gascoyne R.D., Craig R.W. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood. 2001;97:3902–3909. doi: 10.1182/blood.V97.12.3902. PubMed DOI

Cho-Vega J.H., Rassidakis G.Z., Admirand J.H., Oyarzo M., Ramalingam P., Paraguya A., McDonnell T.J., Amin H.M., Medeiros L.J. MCL-1 expression in B-cell non-Hodgkin’s lymphomas. Hum. Pathol. 2004;35:1095–1100. doi: 10.1016/j.humpath.2004.04.018. PubMed DOI

Agarwal B., Naresh K.N. Bcl-2 family of proteins in indolent B-cell non-Hodgkin’s lymphoma: Study of 116 cases. Am. J. Hematol. 2002;70:278–282. doi: 10.1002/ajh.10139. PubMed DOI

Wenzel S.S., Grau M., Mavis C., Hailfinger S., Wolf A., Madle H., Deeb G., Dorken B., Thome M., Lenz P., et al. MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma. Leukemia. 2013;27:1381–1390. doi: 10.1038/leu.2012.367. PubMed DOI

Katz S.G., Labelle J.L., Meng H., Valeriano R.P., Fisher J.K., Sun H., Rodig S.J., Kleinstein S.H., Walensky L.D. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells. Blood. 2014;123:884–893. doi: 10.1182/blood-2013-04-499079. PubMed DOI PMC

Prukova D., Andera L., Nahacka Z., Karolova J., Svaton M., Klanova M., Havranek O., Soukup J., Svobodova K., Zemanova Z., et al. Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. Clin. Cancer Res. 2019;25:4455–4465. doi: 10.1158/1078-0432.CCR-18-3275. PubMed DOI

Wang J.D., Katz S.G., Morgan E.A., Yang D.T., Pan X., Xu M.L. Proapoptotic protein BIM as a novel prognostic marker in mantle cell lymphoma. Hum. Pathol. 2019;93:54–64. doi: 10.1016/j.humpath.2019.08.008. PubMed DOI PMC

Pfeifer M., Grau M., Lenze D., Wenzel S.S., Wolf A., Wollert-Wulf B., Dietze K., Nogai H., Storek B., Madle H., et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. USA. 2013;110:12420–12425. doi: 10.1073/pnas.1305656110. PubMed DOI PMC

Datta S.R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., Greenberg M.E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–241. doi: 10.1016/S0092-8674(00)80405-5. PubMed DOI

Davis R.E., Brown K.D., Siebenlist U., Staudt L.M. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 2001;194:1861–1874. doi: 10.1084/jem.194.12.1861. PubMed DOI PMC

Ngo V.N., Davis R.E., Lamy L., Yu X., Zhao H., Lenz G., Lam L.T., Dave S., Yang L., Powell J., et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature. 2006;441:106–110. doi: 10.1038/nature04687. PubMed DOI

Lenz G., Davis R.E., Ngo V.N., Lam L., George T.C., Wright G.W., Dave S.S., Zhao H., Xu W., Rosenwald A., et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319:1676–1679. doi: 10.1126/science.1153629. PubMed DOI

Ngo V.N., Young R.M., Schmitz R., Jhavar S., Xiao W., Lim K.H., Kohlhammer H., Xu W., Yang Y., Zhao H., et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–119. doi: 10.1038/nature09671. PubMed DOI PMC

Willis T.G., Jadayel D.M., Du M.Q., Peng H., Perry A.R., Abdul-Rauf M., Price H., Karran L., Majekodunmi O., Wlodarska I., et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell. 1999;96:35–45. doi: 10.1016/S0092-8674(00)80957-5. PubMed DOI

Lucas P.C., Yonezumi M., Inohara N., McAllister-Lucas L.M., Abazeed M.E., Chen F.F., Yamaoka S., Seto M., Nunez G. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J. Biol. Chem. 2001;276:19012–19019. doi: 10.1074/jbc.M009984200. PubMed DOI

Varfolomeev E., Wayson S.M., Dixit V.M., Fairbrother W.J., Vucic D. The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2. J. Biol. Chem. 2006;281:29022–29029. doi: 10.1074/jbc.M605116200. PubMed DOI

Luo J.L., Kamata H., Karin M. IKK/NF-kappaB signaling: Balancing life and death--a new approach to cancer therapy. J. Clin. Investig. 2005;115:2625–2632. doi: 10.1172/JCI26322. PubMed DOI PMC

Xu-Monette Z.Y., Medeiros L.J., Li Y., Orlowski R.Z., Andreeff M., Bueso-Ramos C.E., Greiner T.C., McDonnell T.J., Young K.H. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 2012;119:3668–3683. doi: 10.1182/blood-2011-11-366062. PubMed DOI PMC

Xu-Monette Z.Y., Wu L., Visco C., Tai Y.C., Tzankov A., Liu W.M., Montes-Moreno S., Dybkaer K., Chiu A., Orazi A., et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: Report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2012;120:3986–3996. doi: 10.1182/blood-2012-05-433334. PubMed DOI PMC

Bea S., Valdes-Mas R., Navarro A., Salaverria I., Martin-Garcia D., Jares P., Gine E., Pinyol M., Royo C., Nadeu F., et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl. Acad. Sci. USA. 2013;110:18250–18255. doi: 10.1073/pnas.1314608110. PubMed DOI PMC

Zenz T., Eichhorst B., Busch R., Denzel T., Habe S., Winkler D., Buhler A., Edelmann J., Bergmann M., Hopfinger G., et al. TP53 mutation and survival in chronic lymphocytic leukemia. J. Clin. Oncol. 2010;28:4473–4479. doi: 10.1200/JCO.2009.27.8762. PubMed DOI

Sander C.A., Yano T., Clark H.M., Harris C., Longo D.L., Jaffe E.S., Raffeld M. p53 mutation is associated with progression in follicular lymphomas. Blood. 1993;82:1994–2004. doi: 10.1182/blood.V82.7.1994.1994. PubMed DOI

Lo Coco F., Gaidano G., Louie D.C., Offit K., Chaganti R.S., Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993;82:2289–2295. doi: 10.1182/blood.V82.8.2289.2289. PubMed DOI

Nakano K., Vousden K.H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell. 2001;7:683–694. doi: 10.1016/S1097-2765(01)00214-3. PubMed DOI

Villunger A., Michalak E.M., Coultas L., Mullauer F., Bock G., Ausserlechner M.J., Adams J.M., Strasser A. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science. 2003;302:1036–1038. doi: 10.1126/science.1090072. PubMed DOI

Klasa R.J., Gillum A.M., Klem R.E., Frankel S.R. Oblimersen Bcl-2 antisense: Facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev. 2002;12:193–213. doi: 10.1089/108729002760220798. PubMed DOI

O’Brien S., Moore J.O., Boyd T.E., Larratt L.M., Skotnicki A.B., Koziner B., Chanan-Khan A.A., Seymour J.F., Gribben J., Itri L.M., et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J. Clin. Oncol. 2009;27:5208–5212. doi: 10.1200/JCO.2009.22.5748. PubMed DOI PMC

Nguyen M., Marcellus R.C., Roulston A., Watson M., Serfass L., Murthy Madiraju S.R., Goulet D., Viallet J., Belec L., Billot X., et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc. Natl. Acad. Sci. USA. 2007;104:19512–19517. doi: 10.1073/pnas.0709443104. PubMed DOI PMC

Konopleva M., Watt J., Contractor R., Tsao T., Harris D., Estrov Z., Bornmann W., Kantarjian H., Viallet J., Samudio I., et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax) Cancer Res. 2008;68:3413–3420. doi: 10.1158/0008-5472.CAN-07-1919. PubMed DOI PMC

Goy A., Berger M., Ford P., Feldman T., Mato A., Bejot C., Fung H.C. Sequential single-agent obatoclax mesylate (GX15-070MS) followed by combination with rituximab in patients with previously untreated follicular lymphoma. Leuk Lymphoma. 2014;55:2932–2934. doi: 10.3109/10428194.2014.900760. PubMed DOI

Goy A., Hernandez-Ilzaliturri F.J., Kahl B., Ford P., Protomastro E., Berger M. A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma. Leuk Lymphoma. 2014;55:2761–2768. doi: 10.3109/10428194.2014.907891. PubMed DOI PMC

O’Brien S.M., Claxton D.F., Crump M., Faderl S., Kipps T., Keating M.J., Viallet J., Cheson B.D. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113:299–305. doi: 10.1182/blood-2008-02-137943. PubMed DOI PMC

Brown J.R., Tesar B., Yu L., Werner L., Takebe N., Mikler E., Reynolds H.M., Thompson C., Fisher D.C., Neuberg D., et al. Obatoclax in combination with fludarabine and rituximab is well-tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56:3336–3342. doi: 10.3109/10428194.2015.1048441. PubMed DOI

Oltersdorf T., Elmore S.W., Shoemaker A.R., Armstrong R.C., Augeri D.J., Belli B.A., Bruncko M., Deckwerth T.L., Dinges J., Hajduk P.J., et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–681. doi: 10.1038/nature03579. PubMed DOI

Tse C., Shoemaker A.R., Adickes J., Anderson M.G., Chen J., Jin S., Johnson E.F., Marsh K.C., Mitten M.J., Nimmer P., et al. ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–3428. doi: 10.1158/0008-5472.CAN-07-5836. PubMed DOI

Wilson W.H., O’Connor O.A., Czuczman M.S., LaCasce A.S., Gerecitano J.F., Leonard J.P., Tulpule A., Dunleavy K., Xiong H., Chiu Y.L., et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: A phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11:1149–1159. doi: 10.1016/S1470-2045(10)70261-8. PubMed DOI PMC

Roberts A.W., Seymour J.F., Brown J.R., Wierda W.G., Kipps T.J., Khaw S.L., Carney D.A., He S.Z., Huang D.C., Xiong H., et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: Results of a phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol. 2012;30:488–496. doi: 10.1200/JCO.2011.34.7898. PubMed DOI PMC

Vogler M., Hamali H.A., Sun X.M., Bampton E.T., Dinsdale D., Snowden R.T., Dyer M.J., Goodall A.H., Cohen G.M. BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood. 2011;117:7145–7154. doi: 10.1182/blood-2011-03-344812. PubMed DOI

Zhang H., Nimmer P.M., Tahir S.K., Chen J., Fryer R.M., Hahn K.R., Iciek L.A., Morgan S.J., Nasarre M.C., Nelson R., et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007;14:943–951. doi: 10.1038/sj.cdd.4402081. PubMed DOI

Kipps T.J., Eradat H., Grosicki S., Catalano J., Cosolo W., Dyagil I.S., Yalamanchili S., Chai A., Sahasranaman S., Punnoose E., et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56:2826–2833. doi: 10.3109/10428194.2015.1030638. PubMed DOI PMC

Souers A.J., Leverson J.D., Boghaert E.R., Ackler S.L., Catron N.D., Chen J., Dayton B.D., Ding H., Enschede S.H., Fairbrother W.J., et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 2013;19:202–208. doi: 10.1038/nm.3048. PubMed DOI

Roberts A.W., Davids M.S., Pagel J.M., Kahl B.S., Puvvada S.D., Gerecitano J.F., Kipps T.J., Anderson M.A., Brown J.R., Gressick L., et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N. Engl. J. Med. 2016;374:311–322. doi: 10.1056/NEJMoa1513257. PubMed DOI PMC

Stilgenbauer S., Eichhorst B., Schetelig J., Coutre S., Seymour J.F., Munir T., Puvvada S.D., Wendtner C.M., Roberts A.W., Jurczak W., et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–778. doi: 10.1016/S1470-2045(16)30019-5. PubMed DOI

Seymour J.F., Ma S., Brander D.M., Choi M.Y., Barrientos J., Davids M.S., Anderson M.A., Beaven A.W., Rosen S.T., Tam C.S., et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: A phase 1b study. Lancet Oncol. 2017;18:230–240. doi: 10.1016/S1470-2045(17)30012-8. PubMed DOI PMC

Seymour J.F., Kipps T.J., Eichhorst B., Hillmen P., D’Rozario J., Assouline S., Owen C., Gerecitano J., Robak T., De la Serna J., et al. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N. Engl. J. Med. 2018;378:1107–1120. doi: 10.1056/NEJMoa1713976. PubMed DOI

Flinn I.W., Gribben J.G., Dyer M.J.S., Wierda W., Maris M.B., Furman R.R., Hillmen P., Rogers K.A., Iyer S.P., Quillet-Mary A., et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019;133:2765–2775. doi: 10.1182/blood-2019-01-896290. PubMed DOI PMC

Fischer K., Al-Sawaf O., Bahlo J., Fink A.M., Tandon M., Dixon M., Robrecht S., Warburton S., Humphrey K., Samoylova O., et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N. Engl. J. Med. 2019;380:2225–2236. doi: 10.1056/NEJMoa1815281. PubMed DOI

Zelenetz A.D., Salles G., Mason K.D., Casulo C., Le Gouill S., Sehn L.H., Tilly H., Cartron G., Chamuleau M.E.D., Goy A., et al. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial. Blood. 2019;133:1964–1976. doi: 10.1182/blood-2018-11-880526. PubMed DOI PMC

Morschhauser F., Feugier P., Flinn I.W., Gasiorowski R.E., Greil R., Illés Á., Johnson N.A., Larouche J.-F., Lugtenburg P.J., Patti C., et al. Venetoclax Plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) Improves Outcomes in BCL2-Positive First-Line Diffuse Large B-Cell Lymphoma (DLBCL): First Safety, Efficacy and Biomarker Analyses from the Phase II CAVALLI Study. Blood. 2018;132:782. PubMed

Zinzani P.L., Topp M.S., Yuen S.L., Rusconi C., Fleury I., Pro B., Gritti G., Crump M., Hsu W., Punnoose E.A., et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood. 2016;128:617. doi: 10.1182/blood.V128.22.617.617. DOI

Tam C.S., Anderson M.A., Pott C., Agarwal R., Handunnetti S., Hicks R.J., Burbury K., Turner G., Di Iulio J., Bressel M., et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N. Engl. J. Med. 2018;378:1211–1223. doi: 10.1056/NEJMoa1715519. PubMed DOI

Castillo J.J., Gustine J., Meid K., Dubeau T., Keezer A., Allan J.N., Furman R.R., Siddiqi T., Advani R., Lam J., et al. Multicenter Prospective Phase II Study of Venetoclax in Patients with Previously Treated Waldenstrom Macroglobulinemia. Blood. 2018;132:2888. doi: 10.1182/blood-2018-99-112325. DOI

Klanova M., Andera L., Brazina J., Svadlenka J., Benesova S., Soukup J., Prukova D., Vejmelkova D., Jaksa R., Helman K., et al. Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma. Clin. Cancer Res. 2015 doi: 10.1158/1078-0432.CCR-15-1191. PubMed DOI

Li L., Pongtornpipat P., Tiutan T., Kendrick S.L., Park S., Persky D.O., Rimsza L.M., Puvvada S.D., Schatz J.H. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia. 2015;29:1702–1712. doi: 10.1038/leu.2015.99. PubMed DOI PMC

Dengler M.A., Teh C.E., Thijssen R., Gangoda L., Lan P., Herold M.J., Gray D.H., Kelly G.L., Roberts A.W., Adams J.M. Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma. Oncogene. 2020;39:2009–2023. doi: 10.1038/s41388-019-1122-x. PubMed DOI

Yi X., Sarkar A., Kismali G., Aslan B., Ayres M., Iles L.R., Keating M.J., Wierda W., Long J.P., Bertilaccio M.T.S., et al. AMG-176, an Mcl-1 antagonist, shows preclinical efficacy in chronic lymphocytic leukemia. Clin. Cancer Res. 2020 doi: 10.1158/1078-0432.CCR-19-1397. PubMed DOI PMC

Tron A.E., Belmonte M.A., Adam A., Aquila B.M., Boise L.H., Chiarparin E., Cidado J., Embrey K.J., Gangl E., Gibbons F.D., et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun. 2018;9:5341. doi: 10.1038/s41467-018-07551-w. PubMed DOI PMC

Khan S., Zhang X., Lv D., Zhang Q., He Y., Zhang P., Liu X., Thummuri D., Yuan Y., Wiegand J.S., et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 2019;25:1938–1947. doi: 10.1038/s41591-019-0668-z. PubMed DOI PMC

Phillips D.C., Xiao Y., Lam L.T., Litvinovich E., Roberts-Rapp L., Souers A.J., Leverson J.D. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199) Blood Cancer J. 2016;6:e403. doi: 10.1038/bcj.2016.12. PubMed DOI PMC

Del Gaizo Moore V., Brown J.R., Certo M., Love T.M., Novina C.D., Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J. Clin. Investig. 2007;117:112–121. doi: 10.1172/JCI28281. PubMed DOI PMC

De Jong M.R.W., Langendonk M., Reitsma B., Nijland M., van den Berg A., Ammatuna E., Visser L., van Meerten T. Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma. Int. J. Mol. Sci. 2019;20:6036. doi: 10.3390/ijms20236036. PubMed DOI PMC

Touzeau C., Dousset C., Bodet L., Gomez-Bougie P., Bonnaud S., Moreau A., Moreau P., Pellat-Deceunynck C., Amiot M., Le Gouill S. ABT-737 induces apoptosis in mantle cell lymphoma cells with a Bcl-2high/Mcl-1low profile and synergizes with other antineoplastic agents. Clin. Cancer Res. 2011;17:5973–5981. doi: 10.1158/1078-0432.CCR-11-0955. PubMed DOI

Choudhary G.S., Al-Harbi S., Mazumder S., Hill B.T., Smith M.R., Bodo J., Hsi E.D., Almasan A. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593. doi: 10.1038/cddis.2014.525. PubMed DOI PMC

Liu Y., Mondello P., Erazo T., Tannan N.B., Asgari Z., de Stanchina E., Nanjangud G., Seshan V.E., Wang S., Wendel H.G., et al. NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proc. Natl. Acad. Sci. USA. 2018;115:12034–12039. doi: 10.1073/pnas.1806928115. PubMed DOI PMC

Jin S., Cojocari D., Purkal J.J., Popovic R., Talaty N.N., Xiao Y., Solomon L.R., Boghaert E.R., Leverson J.D., Phillips D.C. 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-mediated Apoptosis. Clin. Cancer Res. 2020 doi: 10.1158/1078-0432.CCR-19-1900. PubMed DOI

Chiron D., Bellanger C., Papin A., Tessoulin B., Dousset C., Maiga S., Moreau A., Esbelin J., Trichet V., Chen-Kiang S., et al. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood. 2016;128:2808–2818. doi: 10.1182/blood-2016-06-720490. PubMed DOI

Guieze R., Liu V.M., Rosebrock D., Jourdain A.A., Hernandez-Sanchez M., Martinez Zurita A., Sun J., Ten Hacken E., Baranowski K., Thompson P.A., et al. Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies. Cancer Cell. 2019;36:369–384. doi: 10.1016/j.ccell.2019.08.005. PubMed DOI PMC

Fresquet V., Rieger M., Carolis C., Garcia-Barchino M.J., Martinez-Climent J.A. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123:4111–4119. doi: 10.1182/blood-2014-03-560284. PubMed DOI

Tausch E., Close W., Dolnik A., Bloehdorn J., Chyla B., Bullinger L., Dohner H., Mertens D., Stilgenbauer S. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica. 2019;104:e434–e437. doi: 10.3324/haematol.2019.222588. PubMed DOI PMC

Weiss J., Peifer M., Herling C.D., Frenzel L.P., Hallek M. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia (Comment to Tausch et al.) Haematologica. 2019;104:e540. doi: 10.3324/haematol.2019.232835. PubMed DOI PMC

Blombery P., Anderson M.A., Gong J.N., Thijssen R., Birkinshaw R.W., Thompson E.R., Teh C.E., Nguyen T., Xu Z., Flensburg C., et al. Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia. Cancer Discov. 2019;9:342–353. doi: 10.1158/2159-8290.CD-18-1119. PubMed DOI

Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas