Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Molecular Targets for Therapy

p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells

Leukemia volume 25, pages 761–769 (2011)Cite this article

Subjects

Abstract

Philadelphia chromosome positive chronic myeloid leukemia has a progressive course starting in a benign phase and terminating in a blastic phase. In this study, we show that human homolog double minute 2 (HDM2) inhibition, with MI-219—a novel compound, and consequently p53 stabilization induce chronic myeloid leukemia (CML) blast crisis cells to undergo apoptosis regardless of the presence of the T315I mutation in the BCR–ABL kinase domain. The response to MI-219 is associated with the downregulation of c-Myc and the induction of p21WAF1. The p53 target and pro-apoptotic proteins PUMA, Noxa and Bax are induced, whereas full length Bid protein decreases with increased activity of pro-apoptotic cleaved Bid, and decrease of Mcl-1 is observed by increased caspase activity. CD95/FAS (FAS antigen) receptor is also induced by MI-219, indicating that both intrinsic and extrinsic apoptotic responses are transcriptionally induced. In addition, p53 protein accumulates in the mitochondrial fraction of treated cells involved in transcription-independent induction of apoptosis. We conclude that HDM-2 inhibition with MI-219 effectively induces p53-dependent apoptosis in most blast crisis CML cells, with or without BCR–ABL mutation(s).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Nowell PC . Discovery of the Philadelphia chromosome: a personal perspective. J Clin Invest 2007; 117: 2033–2035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rowley JD . Chromosome translocations: dangerous liaisons revisited. Nat Rev Cancer 2001; 1: 245–250.

    Article  CAS  PubMed  Google Scholar 

  3. Matulonis U, Salgia R, Okuda K, Druker B, Griffin JD . Interleukin-3 and p210 BCR/ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid cell line. Exp Hematol 1993; 21: 1460–1466.

    CAS  PubMed  Google Scholar 

  4. Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 1997; 16: 6151–6161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xie S, Lin H, Sun T, Arlinghaus RB . Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 2002; 21: 7137–7146.

    Article  CAS  PubMed  Google Scholar 

  6. Carlesso N, Frank DA, Griffin JD . Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J Exp Med 1996; 183: 811–820.

    Article  CAS  PubMed  Google Scholar 

  7. Perrotti D, Neviani P . From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows the way. Clin Cancer Res 2007; 13: 1638–1642.

    Article  CAS  PubMed  Google Scholar 

  8. Azam M, Latek RR, Daley GQ . Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003; 112: 831–843.

    Article  CAS  PubMed  Google Scholar 

  9. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L . Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 2003; 4: 75–85.

    Article  PubMed  Google Scholar 

  10. Toledo F, Wahl GM . Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006; 6: 909–923.

    Article  CAS  PubMed  Google Scholar 

  11. Di Bacco A, Keeshan K, McKenna SL, Cotter TG . Molecular abnormalities in chronic myeloid leukemia: deregulation of cell growth and apoptosis. Oncologist 2000; 5: 405–415.

    Article  CAS  PubMed  Google Scholar 

  12. Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C et al. BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 2003; 3: 145–160.

    Article  CAS  PubMed  Google Scholar 

  13. Vousden KH, Lane DP . p53 in health and disease. Nat Rev Mol Cell Biol 2007; 8: 275–283.

    Article  CAS  PubMed  Google Scholar 

  14. Shu K-X, Li B, Wu L-X . The p53 network: p53 and its downstream genes. Colloids Surfaces B Biointerfaces 2007; 55: 10–18.

    Article  CAS  PubMed  Google Scholar 

  15. Riley T, Sontag E, Chen P, Levine A . Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 2008; 9: 402–412.

    Article  CAS  PubMed  Google Scholar 

  16. Steele AJ, Prentice AG, Hoffbrand AV, Yogashangary BC, Hart SM, Nacheva EP et al. p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism. Blood 2008; 112: 3827–3834.

    Article  CAS  PubMed  Google Scholar 

  17. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003; 11: 577–590.

    Article  CAS  PubMed  Google Scholar 

  18. Leu JIJ, Dumont P, Hafey M, Murphy ME, George DL . Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 2004; 6: 443–450.

    CAS  PubMed  Google Scholar 

  19. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–848.

    Article  CAS  PubMed  Google Scholar 

  20. Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA 2008; 105: 3933–3938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2&. J Med Chem 2006; 49: 3432–3435.

    Article  CAS  PubMed  Google Scholar 

  22. Shangary S, Wang S . Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 2009; 49: 223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Saddler C, Ouillette P, Kujawski L, Shangary S, Talpaz M, Kaminski M et al. Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia. Blood 2008; 111: 1584–1593.

    Article  CAS  PubMed  Google Scholar 

  24. Brummelkamp TR, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550–553.

    Article  CAS  PubMed  Google Scholar 

  25. Alves NL, Derks IAM, Berk E, Spijker R, van Lier RAW, Eldering E . The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Immunity 2006; 24: 703–716.

    Article  CAS  PubMed  Google Scholar 

  26. Peterson LF, Wang Y, Lo MC, Yan M, Kanbe E, Zhang DE . The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation. Leukemia 2007; 21: 2010–2019.

    Article  CAS  PubMed  Google Scholar 

  27. Keeshan K, Cotter TG, McKenna SL . High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion. Leukemia 2002; 16: 1725–1734.

    Article  CAS  PubMed  Google Scholar 

  28. Vassilev LT . MDM2 inhibitors for cancer therapy. Trends Mol Med 2007; 13: 23–31.

    Article  CAS  PubMed  Google Scholar 

  29. Soldani C, Scovassi AI . Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 2002; 7: 321–328.

    Article  CAS  PubMed  Google Scholar 

  30. Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker BJ . Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem 1994; 269: 22925–22928.

    CAS  PubMed  Google Scholar 

  31. Lau LM, Nugent JK, Zhao X, Irwin MS . HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 2008; 27: 997–1003.

    Article  CAS  PubMed  Google Scholar 

  32. Bartholomeusz GA, Talpaz M, Kapuria V, Kong LY, Wang S, Estrov Z et al. Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood 2007; 109: 3470–3478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood 2005; 105: 3303–3311.

    Article  CAS  PubMed  Google Scholar 

  34. Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B et al. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by bax. Cell 2008; 135: 1074–1084.

    Article  CAS  PubMed  Google Scholar 

  35. Xia M, Knezevic D, Tovar C, Huang B, Heimbrook DC, Vassilev LT . Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation. Cell Cycle 2008; 7: 1604–1612.

    Article  CAS  PubMed  Google Scholar 

  36. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101: 690–698.

    Article  CAS  PubMed  Google Scholar 

  37. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 1998; 188: 2033–2045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ow Y-LP, Green DR, Hao Z, Mak TW . Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol 2008; 9: 532–542.

    Article  CAS  PubMed  Google Scholar 

  39. Vaseva AV, Moll UM . The mitochondrial p53 pathway. Biochim Biophys Acta (BBA)—Bioenergetics 2009; 1787: 414–420.

    Article  CAS  Google Scholar 

  40. Ploner C, Kofler R, Villunger A . Noxa: at the tip of the balance between life and death. Oncogene 2009; 27 (S1): S84–S92.

    Article  Google Scholar 

  41. Selleri C, Sato T, Del Vecchio L, Luciano L, Barrett AJ, Rotoli B et al. Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-alpha in chronic myelogenous leukemia. Blood 1997; 89: 957–964.

    CAS  PubMed  Google Scholar 

  42. Sancho-Martinez I, Martin-Villalba A . Tyrosine phosphorylation and CD95: a FAScinating switch. Cell Cycle 2009; 8: 838–842.

    Article  CAS  PubMed  Google Scholar 

  43. Ametller E, Garcia-Recio S, Costamagna D, Mayordomo C, Fernandez-Nogueira P, Carbo N et al. Tumor promoting effects of CD95 signaling in chemoresistant cells. Mol Cancer 2010; 9: 161.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Druker BJ . Translation of the Philadelphia chromosome into therapy for CML. Blood 2008; 112: 4808–4817.

    Article  CAS  PubMed  Google Scholar 

  45. O'Hare T, Eide CA, Deininger MW . Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007; 110: 2242–2249.

    Article  CAS  PubMed  Google Scholar 

  46. Shah NP, Sawyers CL . Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene 2003; 22: 7389–7395.

    Article  CAS  PubMed  Google Scholar 

  47. Kujawski L, Talpaz M . Strategies for overcoming imatinib resistance in chronic myeloid leukemia. Leuk Lymphoma 2007; 48: 2310–2322.

    Article  CAS  PubMed  Google Scholar 

  48. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.

    Article  CAS  PubMed  Google Scholar 

  49. Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL . Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007; 109: 4016–4019.

    Article  CAS  PubMed  Google Scholar 

  50. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107: 4532–4539.

    Article  CAS  PubMed  Google Scholar 

  51. Seliger B, Papadileris S, Vogel D, Hess G, Brendel C, Storkel S et al. Analysis of the p53 and MDM-2 gene in acute myeloid leukemia. Eur J Haematol 1996; 57: 230–240.

    Article  CAS  PubMed  Google Scholar 

  52. Chang JS, Santhanam R, Trotta R, Neviani P, Eiring AM, Briercheck E et al. High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBP alpha-driven myeloid differentiation. Blood 2007; 110: 994–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Notari M, Neviani P, Santhanam R, Blaser BW, Chang JS, Galietta A et al. A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation. Blood 2006; 107: 2507–2516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Eiring AM, Neviani P, Santhanam R, Oaks JJ, Chang JS, Notari M et al. Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis. Blood 2008; 111: 816–828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Komarova EA, Kondratov RV, Wang K, Christov K, Golovkina TV, Goldblum JR et al. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 2004; 23: 3265–3271.

    Article  CAS  PubMed  Google Scholar 

  56. Liu Y, Elf SE, Miyata Y, Sashida G, Huang G, Di Giandomenico S et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 2009; 4: 37–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Akala OO, Park I-K, Qian D, Pihalja M, Becker MW, Clarke MF . Long-term haematopoietic reconstitution by Trp53−/−p16Ink4a−/−p19Arf−/− multipotent progenitors. Nature 2008; 453: 228–232.

    Article  CAS  PubMed  Google Scholar 

  58. Coll-Mulet L, Iglesias-Serret D, Santidrian AF, Cosialls AM, de Frias M, Castano E et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood 2006; 107: 4109–4114.

    Article  CAS  PubMed  Google Scholar 

  59. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99: 3530–3539.

    CAS  PubMed  Google Scholar 

  60. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937.

    Article  CAS  PubMed  Google Scholar 

  61. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    Article  CAS  PubMed  Google Scholar 

  62. Abrahamsson AE, Geron I, Gotlib J, Dao K-HT, Barroga CF, Newton IG et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci USA 2009; 106: 3925–3929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007; 12: 528–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458: 776–779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Stecca B, Ruiz i Altaba A . A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J 2009; 28: 663–676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Prowald A, Cronauer MV, von Klot C, Eilers T, Rinnab L, Herrmann T et al. Modulation of beta-catenin-mediated TCF-signalling in prostate cancer cell lines by wild-type and mutant p53. Prostate 2007; 67: 1751–1760.

    Article  CAS  PubMed  Google Scholar 

  67. Rother K, Johne C, Spiesbach K, Haugwitz U, Tschop K, Wasner M et al. Identification of Tcf-4 as a transcriptional target of p53 signalling. Oncogene 2004; 23: 3376–3384.

    Article  CAS  PubMed  Google Scholar 

  68. Abe Y, Oda-Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K et al. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci USA 2008; 105: 4838–4843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood 2010; 116: 71–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    L F Peterson, E Mitrikeska, D Giannola, Y Lui, H Sun, D Bixby, S N Malek, N J Donato, S Wang & M Talpaz

  2. Department of Internal Medicine Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

    L F Peterson, E Mitrikeska, D Giannola, Y Lui, H Sun, D Bixby, S N Malek, N J Donato & M Talpaz

  3. Department of Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA

    S Wang

Authors
  1. L F Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Mitrikeska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Giannola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Lui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Bixby
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S N Malek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N J Donato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Talpaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Talpaz.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peterson, L., Mitrikeska, E., Giannola, D. et al. p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells. Leukemia 25, 761–769 (2011). https://doi.org/10.1038/leu.2011.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.7

Keywords

This article is cited by

Search

Advanced search

Quick links