Current Hematologic Malignancy Reports

, Volume 13, Issue 4, pp 256–264 | Cite as

Shutting Down Acute Myeloid Leukemia and Myelodysplastic Syndrome with BCL-2 Family Protein Inhibition

  • Prashant Sharma
  • Daniel A PollyeaEmail author
Myelodysplastic Syndromes (M Savona, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Myelodysplastic Syndromes


Purpose of Review

Apoptosis results from the interaction between pro- and anti-apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma-2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax.

Recent Findings

Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naïve population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting.


BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies.


BCL-2 Acute myeloid leukemia Myelodysplastic syndrome AML MDS Apoptosis Venetoclax 


Compliance with Ethical Standards

Conflict of Interest

Daniel A Pollyea served as an advisory board member for Celyad, Agios, Celgene, Abbvie, Argenx, Pfizer, Curis, Takeda, and Servier, and received research funding from Agios and Pfizer. Prashant Sharma declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance•• Of major Importance

  1. 1.
    Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–27.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Gangat N, Patnaik MM, Tefferi A. Myelodysplastic syndromes: contemporary review and how we treat. Am J Hematol. 2016;91(1):76–89.CrossRefPubMedGoogle Scholar
  3. 3.
    Sekeres MA. The epidemiology of myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010;24(2):287–94.CrossRefPubMedGoogle Scholar
  4. 4.
    Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820–9.Google Scholar
  6. 6.
    SEER. Acute Myeloid Leukemia - Cancer Stat Facts 2017 [Available from:
  7. 7.
    De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179–87.CrossRefPubMedGoogle Scholar
  9. 9.
    Estey EH. Therapeutic options for acute myelogenous leukemia. Cancer. 2001;92(5):1059–73.CrossRefPubMedGoogle Scholar
  10. 10.
    Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091–6.PubMedGoogle Scholar
  12. 12.
    Jilg S, Reidel V, Muller-Thomas C, Konig J, Schauwecker J, Hockendorf U, et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia. 2016;30(1):112–23.CrossRefPubMedGoogle Scholar
  13. 13.
    Arellano ML, Borthakur G, Berger M, Luer J, Raza A. A phase II, multicenter, open-label study of obatoclax mesylate in patients with previously untreated myelodysplastic syndromes with anemia or thrombocytopenia. Clin Lymphoma Myeloma Leuk. 2014;14(6):534–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88.CrossRefPubMedGoogle Scholar
  15. 15.
    Baev DV, Krawczyk J, M OD, Szegezdi E. The BH3-mimetic ABT-737 effectively kills acute myeloid leukemia initiating cells. Leukemia Research Reports. 2014;3(2):79–82.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    •• Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329–41. This study demonstrated that LSCs were characterized by low levels of reactive oxygen species (ROS-low), that ROS-low LSCs aberrantly overexpressed BCL-2, and that BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated LSCs.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science (New York, NY). 1984;226(4678):1097–9.CrossRefGoogle Scholar
  18. 18.
    Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986;47(1):19–28.CrossRefPubMedGoogle Scholar
  19. 19.
    Dai H, Meng XW, Kaufmann SH. BCL2 Family, Mitochondrial Apoptosis, and Beyond. Cancer Transl Med. 2017;2(1):7–20.CrossRefGoogle Scholar
  20. 20.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205–19.CrossRefGoogle Scholar
  22. 22.
    Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science (New York, NY). 1998;281(5381):1305–8.CrossRefGoogle Scholar
  23. 23.
    Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4(2):139–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Yan N, Shi Y. Mechanisms of apoptosis through structural biology. Annu Rev Cell Dev Biol. 2005;21:35–56.CrossRefPubMedGoogle Scholar
  25. 25.
    Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16(4):273–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Reed JC. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol. 1997;34(4 Suppl 5):9–19.PubMedGoogle Scholar
  27. 27.
    Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9(1):47–59.CrossRefPubMedGoogle Scholar
  28. 28.
    Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440–2.CrossRefPubMedGoogle Scholar
  29. 29.
    Pollyea DA, Jordan CT. Therapeutic targeting of acute myeloid leukemia stem cells. Blood. 2017;129(12):1627–35.CrossRefPubMedGoogle Scholar
  30. 30.
    Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253–61.CrossRefGoogle Scholar
  31. 31.
    Warner JK, Wang JC, Hope KJ, Jin L, Dick JE. Concepts of human leukemic development. Oncogene. 2004;23(43):7164–77.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang HG, Reed JC. Mechanisms of Bcl-2 protein function. Histol Histopathol. 1998;13(2):521–30.PubMedGoogle Scholar
  33. 33.
    Banker DE, Radich J, Becker A, Kerkof K, Norwood T, Willman C, et al. The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. Clin Cancer Res. 1998;4(12):3051–62.PubMedGoogle Scholar
  34. 34.
    Konopleva M, Tari AM, Estrov Z, Harris D, Xie Z, Zhao S, et al. Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood. 2000;95(12):3929–38.PubMedGoogle Scholar
  35. 35.
    Marcucci G, Byrd JC, Dai G, Klisovic MI, Kourlas PJ, Young DC, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003;101(2):425–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Marcucci G, Stock W, Dai G, Klisovic RB, Liu S, Klisovic MI, et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(15):3404–11.CrossRefGoogle Scholar
  37. 37.
    Moore J, Seiter K, Kolitz J, Stock W, Giles F, Kalaycio M, et al. A phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse. Leuk Res. 2006;30(7):777–83.CrossRefPubMedGoogle Scholar
  38. 38.
    Marcucci G, Moser W, Blum W, Stock M, Wetzler J, Kolitz JE, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients > 60 years old. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:7012.CrossRefGoogle Scholar
  39. 39.
    Schimmer AD, O'Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(24):8295–301.CrossRefPubMedGoogle Scholar
  40. 40.
    Schimmer AD, Raza A, Carter TH, Claxton D, Erba H, DeAngelo DJ, et al. A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia. PLoS One. 2014;9(10):e108694.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Zhang H, Nimmer PM, Tahir SK, Chen J, Fryer RM, Hahn KR, et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007;14(5):943–51.PubMedGoogle Scholar
  42. 42.
    Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128(6):1173–86.CrossRefPubMedGoogle Scholar
  44. 44.
    Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, 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(12):1149–59.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Schoenwaelder SM, Jarman KE, Gardiner EE, Hua M, Qiao J, White MJ, et al. Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood. 2011;118(6):1663–74.CrossRefPubMedGoogle Scholar
  46. 46.
    Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016;6(10):1106–17.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178–84.CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    DiNardo CD, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401–7.CrossRefPubMedGoogle Scholar
  49. 49.
    • Ho TC, LaMere M, Stevens BM, Ashton JM, Myers JR, O'Dwyer KM, et al. Evolution of acute myelogenous leukemia stem cell properties after treatment and progression. Blood 2016;128(13):1671–8. This study showed the evolution of the LSCs showing increases in LSC frequency and heterogeneity at relapse. This study showed that LSC-directed therapies, like with venetoclax, would be more effective in up-front setting rather than after disease relapse.Google Scholar
  50. 50.
    Tsao T, Shi Y, Kornblau S, Lu H, Konoplev S, Antony A, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91(12):1861–70.CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Bogenberger JM, Delman D, Hansen N, Valdez R, Fauble V, Mesa RA, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Bogenberger JM, Kornblau SM, Pierceall WE, Lena R, Chow D, Shi CX, et al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia. 2014;28(8):1657–65.CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    • DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216–28. This ongoing study showed that venetoclax plus hypomethylating agent therapy is well-tolerated regimen with promising activity in elderly patient population in upfront setting.CrossRefPubMedGoogle Scholar
  54. 54.
    DiNardo CD, Pollyea DA, Jonas BA, Konopleva M, Pullarkat V, Wei A, et al. Updated Safety and Efficacy of Venetoclax with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia. Blood. 2017;130(Suppl 1):2628.Google Scholar
  55. 55.
    Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leuk Res Rep. 2016;6:1–7.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, et al. Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes. Blood. 2017;130(Suppl 1):890.Google Scholar
  57. 57.
    Niu X, Zhao J, Ma J, Xie C, Edwards H, Wang G, et al. Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016;22(17):4440–51.CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Pan R, Ruvolo VR, Wei J, Konopleva M, Reed JC, Pellecchia M, et al. Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor (-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood. 2015;126(3):363–72.CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Bogenberger J, Whatcott C, Hansen N, Delman D, Shi CX, Kim W, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017;8:107206–22.CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle. 2006;5(23):2778–86.CrossRefPubMedGoogle Scholar
  61. 61.
    Daver N, Pollyea DA, Yee KWL, Fenaux P, Brandwein JM, Vey N, et al. Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML. Blood. 2017;130(Suppl 1):813.Google Scholar
  62. 62.
    Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017;58:1–17.CrossRefPubMedGoogle Scholar
  63. 63.
    Rajapaksa R, Ginzton N, Rott LS, Greenberg PL. Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. Blood. 1996;88(11):4275–87.PubMedGoogle Scholar
  64. 64.
    Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Schimmer AD. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer. 2007;7(2):118–29.CrossRefPubMedGoogle Scholar
  65. 65.
    Invernizzi R, Pecci A, Bellotti L, Ascari E. Expression of p53, bcl-2 and ras oncoproteins and apoptosis levels in acute leukaemias and myelodysplastic syndromes. Leuk Lymphoma. 2001;42(3):481–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood. 2000;96(12):3932–8.PubMedGoogle Scholar
  67. 67.
    Mali RS, Lasater EA, Doyle K, Malla R, Boghaert E, Souers A, et al. FLT3-ITD activation mediates resistance to the BCL-2 selective antagonist, venetoclax, in FLT3-ITD mutant AML models. 2017.Google Scholar
  68. 68.
    Bruedigam C, Bagger FO, Heidel FH, Kuhn CP, Guignes S, Song A, et al. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell. 2014;15(6):775–90.CrossRefPubMedCentralPubMedGoogle Scholar
  69. 69.
    Rusbuldt JJ, Luistro L, Chin D, Smith M, Wong A, Romero M, et al. Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosisin vitro and increases survival in vivo in acute myeloid leukemia. Cancer Res. 2017;77(Suppl 13):1101.CrossRefGoogle Scholar
  70. 70.
    Tauchi T, Okabe S, Katagiri S, Tanaka Y, Ohyashiki K. Combining Effects of the SMO Inhibitor and BCL-2 Inhibitor in MDS-Derived Induced Potent Stem Cells (iPSC). Blood. 2017;130(Suppl 1):1249.Google Scholar
  71. 71.
    • Kurtz SE, Eide CA, Kaempf A, Khanna V, Savage SL, Rofelty A, et al. Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies. Proc Natl Acad Sci U S A. 2017;114(36):E7554–e63. In this study, several combinations of kinase inhibitors with venetoclax were effective in inhibiting myeloid-derived cells showing that novel combination therapies with venetoclax could be avenues for future AML clinical trials.CrossRefPubMedCentralPubMedGoogle Scholar
  72. 72.
    Ebrahim AS, Kandouz M, Liddane A, Sabbagh H, Hou Y, Li C, et al. PNT2258, a novel deoxyribonucleic acid inhibitor, induces cell cycle arrest and apoptosis via a distinct mechanism of action: a new class of drug for non-Hodgkin’s lymphoma. Oncotarget. 2016;7(27):42374–84.CrossRefPubMedCentralPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Division of HematologyUniversity of Colorado School of MedicineAuroraUSA

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