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Potential role of Wnt/β-catenin signaling in blastic transformation of chronic myeloid leukemia: cross talk between β-catenin and BCR-ABL

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Tumor Biology

Abstract

Chronic myeloid leukemia (CML) results from malignant transformation of hematopoietic stem cells induced by the BCR-ABL oncogene. Transformation from chronic to blastic phase is the lethal step in CML. Leukemic stem cells (LSCs) are the basic reason for blastic transformation. It has been shown that Wnt/β-catenin signaling contributes to the self-renewal capacity and proliferation of LSCs in CML. However, the role of Wnt/β-catenin signaling in blastic transformation of CML is still obscure. Here, we explored the relationship between BCR-ABL and β-catenin signaling in vitro and in vivo. We found that BCR-ABL stimulated β-catenin via activation of PI3K/AKT signaling in blastic phase CML cells. Inhibition of the kinase activity of BCR-ABL, PI3K, or AKT decreased the level of β-catenin in both K562 cells and a CML mouse model and suppressed the transcription of downstream target genes (c-myc and cyclin D1). In addition, inhibition of the BCR-ABL/PI3K/AKT pathway delayed the disease progression in the CML mouse model. To further explore the role of β-catenin in the self-renewal and survival of CML LSCs, we established a secondary transplantation CML mouse model. Our data revealed that inhibition of the BCR-ABL/PI3K/AKT pathway reduced the tumor-initiating ability of K562 cells, decreased leukemia cell infiltration into peripheral blood and bone marrow, and prolonged the survival of mice. In conclusion, our data indicate a close relationship between β-catenin and BCR-ABL/PI3K/AKT in blastic phase CML. β-Catenin inhibition may be of therapeutic value by targeting LSCs in combination with a tyrosine kinase inhibitor, which may delay blastic transformation of CML.

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References

  1. Becker MW, Jordan CT. Leukemia stem cells in 2010: current understanding and future directions. Blood Rev. 2011;25(2):75–81.

    Article  CAS  PubMed  Google Scholar 

  2. Rice KN, Jamieson CH. Molecular pathways to CML stem cells. Int J Hematol. 2010;91(5):748–52.

    Article  PubMed  Google Scholar 

  3. Gerber JM, Qin L, Kowalski J, et al. Characterization of chronic myeloid leukemia stem cells. Am J Hemato. 2011;86(1):31–7.

    Article  Google Scholar 

  4. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009;113:1619–30.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7(6):441–53.

    Article  CAS  PubMed  Google Scholar 

  6. Perrotti D, Jamieson C, Goldman J, et al. Chronic myeloid leukemia: mechanisms of blastic transformation [J]. J Clin Invest. 2010;120(7):2254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;341(10):765.

    Article  Google Scholar 

  8. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14):1038–42.

    Article  CAS  PubMed  Google Scholar 

  9. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319–25.

    Article  CAS  PubMed  Google Scholar 

  10. Hu Y, Swerdlow S, Duffy TM, et al. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci U S A. 2006;103(45):16870–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eiring AM, Khorashad JS, Morley K, et al. Advances in the treatment of chronic myeloid leukemia. BMC Med. 2011;9:99.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. International STI571 CML Study Group. N Engl J Med. 2002;346(9):645–52.

    Article  CAS  PubMed  Google Scholar 

  13. Kinstrie R, Copland M. Targeting chronic myeloid leukemia stem cells. Curr Hematol Malig Rep. 2013;8(1):14–21.

    Article  PubMed  Google Scholar 

  14. Malhotra S, Kincade PW. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell. 2009;4:27–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abrahamsson AE, Geron I, Gotlib J, et al. Aberrant regulation of Wnt/beta-catenin pathway mediators in chronic myelogenous leukemia stem cells. Blood (ASH Ann Meet Abstr). 2006;108:2135.

    Google Scholar 

  16. Zhao C, Blum J, Chen A, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cell in vivo. Cancer Cell. 2007;12(4):528–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Staal FJ, Clevers HC. Wnt signaling and hematopoiesis: a WNT-WNT situation. Nat Rev Immunol. 2005;5(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  18. Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005;5(4):311–21.

    Article  CAS  PubMed  Google Scholar 

  19. de Sousa EM, Vermeulen L, Richel D, et al. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17(4):647–53.

    Article  PubMed  Google Scholar 

  20. Dodge ME, Lum L. Drugging the cancer stem cell compartment: lessons learned from the hedgehog and Wnt signal transduction pathways. Annu Rev Pharmacol Toxicol. 2011;51:289–310.

    Article  CAS  PubMed  Google Scholar 

  21. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657–67.

    Article  CAS  PubMed  Google Scholar 

  22. Gunsilius E. Evidence from a leukemia model for maintenance of vascular endothelium by bone marrow-derived endothelial cells. Adv Exp Med Biol. 2003;522:17–24.

    Article  PubMed  Google Scholar 

  23. Coluccia AM, Vacca A, Duñach M, et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 2007;26:1456–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. He XC, Yin T, Grindley JC, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 2007;39(2):189–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Guo W, Lasky 3rd JL, Wu H. Cancer stem cells. Pediatr Res. 2006;59(4 Pt 2):59R–64R.

    Article  PubMed  Google Scholar 

  26. Pool CR. Hematoxylin-eosin staining of OsO4-fixed epon-embedded tissue; prestaining oxidation by acidified H2O2. Stain Technol. 1969;44(2):75–9.

    Article  CAS  PubMed  Google Scholar 

  27. McCubrey JA, Steelman LS, Bertrand FE, et al. Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia. 2014;28(1):15–33.

    Article  CAS  PubMed  Google Scholar 

  28. AS Corbin A, Agarwal M. Loriaux, et al. human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121(1):396–409.

    Article  PubMed  Google Scholar 

  29. Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103(11):4010–22.

    Article  CAS  PubMed  Google Scholar 

  30. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 2004;303(5663):1483–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kolligs FT, Bommer G, Göke B. Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion. 2002;66(3):131–44.

    Article  CAS  PubMed  Google Scholar 

  32. Regmi SC, Park SY, Kim SJ, et al. The anti-tumor activity of succinyl macrolactin A is mediated through the β-catenin destruction complex via the suppression of tankyrase and PI3K/Akt. PLoS One. 2015;10(11):e0141753.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Meng F, Li H, Shi H, et al. MACC1 down-regulation inhibits proliferation and tumourigenicity of nasopharyngeal carcinoma cells through Akt/β-catenin signaling pathway. PLoS One. 2013;8(4):e60821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cross DA, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378(6559):785–9.

    Article  CAS  PubMed  Google Scholar 

  35. Ishibe S, Haydu JE, Togawa A, et al. Cell confluence regulates hepatocyte growth factor-stimulated cell morphogenesis in a beta-catenin-dependent manner. Mol Cell Biol. 2006;26(24):9232–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Voskas D, Ling LS, Woodgett JR. Does GSK-3 provide a shortcut for PI3K activation of Wnt signalling? F1000 Biol Rep. 2010;2:82.

    PubMed  PubMed Central  Google Scholar 

  37. Li C, Zhou C, Wang S, et al. Sensitization of glioma cells to tamoxifen-induced apoptosis by Pl3-kinase inhibitor through the GSK-3β/β-catenin signaling pathway. PLoS One. 2011;6(10):e27053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu C, Li Y, Semenov M, et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108(6):837–47.

    Article  CAS  PubMed  Google Scholar 

  39. Wang PS, Chou FS, Bloomston M, et al. Thiazolidinediones downregulate Wnt/β-catenin signaling via multiple mechanisms in breast cancer cells. J Surg Res. 2009;153(2):210–6.

    Article  CAS  PubMed  Google Scholar 

  40. Shirasaki R, Tashiro H, Oka Y, et al. Chronic myelogenous leukemia cells contribute to the stromal myofibroblasts in leukemic NOD/SCID mouse in vivo. J Oncol. 2012;2012:901783.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Li L, Wang L, Li L, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 2012;21(2):266–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was funded by the Natural Science Foundation of CQ CSTC (cstc2012jjA10013) to Jing Hu and the Special Fund of Chongqing Key Laboratory (CSTC) (2012-2015) to Jing Hu.

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Authors and Affiliations

  1. Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing, China

    Jing Hu, Zhang-Ling Liu, Yi Liu, Zheng-Lan Huang, Hui Li & Wen-Li Feng

  2. Institute of Neuroscience, Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China

    Min Feng

Authors
  1. Jing Hu
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  2. Min Feng
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  3. Zhang-Ling Liu
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  4. Yi Liu
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  5. Zheng-Lan Huang
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  6. Hui Li
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  7. Wen-Li Feng
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Corresponding author

Correspondence to Wen-Li Feng.

Ethics declarations

This study was authorized by the Human Ethics Committee of Chongqing Medical University. All participants provided written informed consent.

The ethical standards includes:

1. Whether the project should be carried out with experimental animal experiment. Whether it could be done with computer simulation, cell culture or lower animals instead of higher animal.

2. Whether the animals used in this experiment are suitable. Whether the number of animals could be reduced through improved design or high quality animals.

3. Whether animals are treated ethically through improving experiment method, adjusting experimental observation index, optimizing the experiment scheme.

4. Whether animal welfare measures are implemented.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Hu, J., Feng, M., Liu, ZL. et al. Potential role of Wnt/β-catenin signaling in blastic transformation of chronic myeloid leukemia: cross talk between β-catenin and BCR-ABL. Tumor Biol. 37, 15859–15872 (2016). https://doi.org/10.1007/s13277-016-5413-3

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  • DOI: https://doi.org/10.1007/s13277-016-5413-3

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