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:

Apoptosis

Activation of apoptosis signaling eliminates CD34+ progenitor cells in blast crisis CML independent of response to tyrosine kinase inhibitors

Leukemia volume 26, pages 788–794 (2012)Cite this article

Abstract

Despite being highly effective for newly diagnosed chronic myeloid leukemia (CML), imatinib not only is inactive against quiescent CML stem cells, but also has limited activity against blast crisis (BC) CML. The relative activity of Bcr-Abl and the expression levels of antiapoptotic proteins in proliferating and quiescent CD34+ BC CML progenitor cells and the effects of targeting antiapoptotic proteins in these cells are unknown. Here we report higher levels of p-CrkL in quiescent than in proliferating CD34+ progenitor cells and comparable expression levels of Bcl-2, Bcl-xL, Mcl-1 and XIAP in the two populations in BC CML. Inhibition of Bcl-2/Bcl-xL by ABT-737 in cells from patients with tyrosine kinase inhibitor (TKI)-resistant BC CML promoted apoptosis in quiescent CD34+ progenitor cells with an efficacy similar to that in proliferating cells. Combination of ABT-737 with imatinib (which decreases Mcl-1 levels) or triptolide (which decreases Mcl-1 and XIAP) synergistically induced death of both proliferating and quiescent CD34+ progenitor cells obtained from TKI-resistant BC CML patients. These results suggest that antiapoptotic proteins are critical targets in BC CML and that activation of apoptosis signaling can eliminate both proliferating and quiescent CD34+ progenitor cells in BC CML, independent of response to TKIs.

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

Similar content being viewed by others

References

  1. Eaves C, Cashman J, Eaves A . Defective regulation of leukemic hematopoiesis in chronic myeloid leukemia. Leuk Res 1998; 22: 1085–1096.

    Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ . Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011; 121: 396–409.

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. 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  Google Scholar 

  6. Holtz MS, Forman SJ, Bhatia R . Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia 2005; 19: 1034–1041.

    Article  CAS  Google Scholar 

  7. Holyoake T, Jiang X, Eaves C, Eaves A . Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999; 94: 2056–2064.

    CAS  PubMed  Google Scholar 

  8. Amarante-Mendes GP, Naekyung KC, Liu L, Huang Y, Perkins CL, Green DR et al. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. Blood 1998; 91: 1700–1705.

    CAS  PubMed  Google Scholar 

  9. 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  Google Scholar 

  10. Aichberger KJ, Mayerhofer M, Krauth MT, Vales A, Kondo R, Derdak S et al. Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia: role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds. Cancer Res 2005; 65: 9436–9444.

    Article  CAS  Google Scholar 

  11. 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: 375–388.

    Article  CAS  Google Scholar 

  12. Kuroda J, Kimura S, Andreeff M, Ashihara E, Kamitsuji Y, Yokota A et al. ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br J Haematol 2007; 140: 181–190.

    PubMed  Google Scholar 

  13. Kuroda J, Kimura S, Strasser A, Andreeff M, O’Reilly LA, Ashihara E et al. Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ 2007; 14: 1667–1677.

    Article  CAS  Google Scholar 

  14. Tauchi T, Sumi M, Nakajima A, Sashida G, Shimamoto T, Ohyashiki K . BCL-2 antisense oligonucleotide genasense is active against imatinib-resistant BCR-ABL-positive cells. Clin Cancer Res 2003; 9: 4267–4273.

    CAS  PubMed  Google Scholar 

  15. Carter BZ, Mak D, Schober WD, Cabreira-Hansen M, Beran M, McQueen T et al. Regulation of survivin expression through bcr-abl/MAPK cascade: targeting survivin overcomes Imatinib resistance and increases Imatinib sensitivity in Imatinib responsive CML cells. Blood 2006; 107: 1555–1563.

    Article  CAS  Google Scholar 

  16. Mak DH, Schober WD, Chen W, Konopleva M, Cortes J, Kantarjian HM et al. Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells. Mol Cancer Ther 2009; 8: 2509–2516.

    Article  CAS  Google Scholar 

  17. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794–2799.

    Article  CAS  Google Scholar 

  18. Beran M, Pisa P, O’Brien S, Kurzrock R, Siciliano M, Cork A et al. Biological properties and growth in SCID mice of a new myelogenous leukemia cell line (KBM-5) derived from chronic myelogenous leukemia cells in the blastic phase. Cancer Res 1993; 53: 3603–3610.

    CAS  PubMed  Google Scholar 

  19. Ricci C, Scappini B, Divoky V, Gatto S, Onida F, Verstovsek S et al. Mutation in the ATP-binding pocket of the ABL kinase domain in an STI571-resistant BCR/ABL-positive cell line. Cancer Res 2002; 62: 5995–5998.

    CAS  PubMed  Google Scholar 

  20. Carter BZ, Mak DH, Shi Y, Schober WD, Wang RY, Konopleva M et al. Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. Cell Cycle 2006; 5: 2223–2229.

    Article  CAS  Google Scholar 

  21. Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R . Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 2002; 99: 3792–3800.

    Article  CAS  Google Scholar 

  22. Itoh K, Tezuka H, Sakoda H, Konno M, Nagata K, Uchiyama T et al. Reproducible establishment of hemopoietic supportive stromal cell lines from murine bone marrow. Exp Hematol 1989; 17: 145–153.

    CAS  PubMed  Google Scholar 

  23. Issaad C, Croisille L, Katz A, Vainchenker W, Coulombel L . A murine stromal cell line allows the proliferation of very primitive human CD34++/CD38- progenitor cells in long-term cultures and semisolid assays. Blood 1993; 81: 2916–2924.

    CAS  PubMed  Google Scholar 

  24. Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M . Stroma cells prevent apoptosis of AML cells by upregulation of anti-apoptotic proteins. Leukemia 2002; 16: 1713–1724.

    Article  CAS  Google Scholar 

  25. Chou TC, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27–55.

    Article  CAS  Google Scholar 

  26. Carter BZ, Mak DH, Schober WD, McQueen T, Harris D, Estrov Z et al. Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells. Blood 2006; 108: 630–637.

    Article  CAS  Google Scholar 

  27. Harousseau JLH, Dombret HD, Pigneux AP, Michallet MM, Brandely MB . Phase I study of F60008, a triptolide derivative, in patients with refractory or relapsing acute leukemias. 13th Congress of the European Hematology Association (EHA) 2008.

Download references

Acknowledgements

We thank Deanna A Alexander, Janis E Smith and Ann M Sutton for helping with the manuscript. Supported in part by grants from the US Department of Defense to BZC and from the National Institutes of Health (P01 CA49639, CA55164 and CA16672) to MA and by the Paul and Mary Haas Chair in Genetics to MA.

Author information

Authors and Affiliations

  1. Department of Leukemia,

    D H Mak, R-Y Wang, W D Schober, M Konopleva, J Cortes, H Kantarjian, M Andreeff & B Z Carter

  2. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D H Mak, R-Y Wang, W D Schober, M Konopleva, J Cortes, H Kantarjian, M Andreeff & B Z Carter

  3. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Konopleva & M Andreeff

Authors
  1. D H Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R-Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W D Schober
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Konopleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Kantarjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Andreeff
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Z Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Z Carter.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mak, D., Wang, RY., Schober, W. et al. Activation of apoptosis signaling eliminates CD34+ progenitor cells in blast crisis CML independent of response to tyrosine kinase inhibitors. Leukemia 26, 788–794 (2012). https://doi.org/10.1038/leu.2011.285

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.285

Keywords

This article is cited by

Search

Advanced search

Quick links