Biochemistry (Moscow)

, Volume 83, Issue 12–13, pp 1448–1458 | Cite as

Alterations in WNT Signaling in Leukemias

  • T. I. Fetisov
  • E. A. Lesovaya
  • M. G. Yakubovskaya
  • K. I. Kirsanov
  • G. A. BelitskyEmail author


The WNT/β–catenin signaling pathway plays an important role in the differentiation and proliferation of hematopoietic cells. In recent years, special attention has been paid to the role of impairments in the WNT signaling path–way in pathogenesis of malignant neoplasms of the hematopoietic system. Disorders in the WNT/β–catenin signaling in leukemias identified to date include hypersensitivity to the WNT ligands, epigenetic repression of WNT antagonists, over–expression of WNT ligands, impaired β–catenin degradation in the cytoplasm, and changes in the activity of the TCF/Lef transcription factors. At the molecular level, these impairments involve overexpression of the FZD protein, hypermethylation of the SFRP, DKK, WiF, Sox, and CXXC gene promoters, overexpression of Lef1 and plakoglobin, mutations in GSK3β, and β–catenin phosphorylation by the BCR–ABL kinase. This review is devoted to the systematization of these data.


leukemias hemopoiesis WNT signaling pathway WNT ligands β–catenin WNT antagonists transcription factors TCF/Lef 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reya, T., and Clevers, H. (2005) Wnt signalling in stem cells and cancer, Nature, 434, 843–850.CrossRefGoogle Scholar
  2. 2.
    Rulifson, I. C., Karnik, S. K., Heiser, P. W., ten Berge, D., Chen, H., Gu, X., Taketo, M. M., Nusse, R., Hebrok, M., and Kim, S. K. (2007) Wnt signaling regulates pancreatic beta cell proliferation, Proc. Natl. Acad. Sci. USA, 104, 6247–6252.CrossRefGoogle Scholar
  3. 3.
    Lu, D., Choi, M. Y., Yu, J., Castro, J. E., Kipps, T. J., and Carson, D. A. (2011) Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells, Proc. Natl. Acad. Sci. USA, 108, 13253–13257.CrossRefGoogle Scholar
  4. 4.
    Zhao, Z. M., Reynolds, A. B., and Gaucher, E. A. (2011) The evolutionary history of the catenin gene family during metazoan evolution, BMC Evol. Biol., 11,198.CrossRefGoogle Scholar
  5. 5.
    Ozawa, M., Baribault, H., and Kemler, R. (1989) The cytoplasmic domain of the cell adhesion molecule uvo–morulin associates with three independent proteins structurally related in different species, EMBO J., 8, 1711–1717.CrossRefGoogle Scholar
  6. 6.
    Cadigan, K. M., and Nusse, R. (1997) Wnt signaling: a common theme in animal development, Genes Dev., 11, 3286–3305.CrossRefGoogle Scholar
  7. 7.
    Koyanagi, M., Haendeler, J., Badorff, C., Brandes, R. P., Hoffmann, J., Pandur, P., Zeiher, A. M., Kuhl, M., and Dimmeler, S. (2005) Non–canonical Wnt signaling enhances differentiation of human circulating progenitor cells to car–diomyogenic cells, J. Biol. Chem., 280, 16838–16842.CrossRefGoogle Scholar
  8. 8.
    Tao, Q., Yokota, C., Puck, H., Kofron, M., Birsoy, B., Yan, D., Asashima, M., Wylie, C. C., Lin, X., and Heasman, J. (2005) Maternal Wnt11 activates the canonical Wnt signaling pathway required for Axis formation in Xenopus embryos, Cell, 120, 857–871.CrossRefGoogle Scholar
  9. 9.
    Cruciat, C. M., and Niehrs, C. (2013) Secreted and trans–membrane Wnt inhibitors and activators, Cold Spring Harb. Perspect. Biol., 5, a015081.CrossRefGoogle Scholar
  10. 10.
    Stamos, J. L., and Weis, W. I. (2013) The β–catenin destruction complex, Cold Spring Harb. Perspect. Biol., 5, a007898.CrossRefGoogle Scholar
  11. 11.
    Liu, C., Li, Y., Semenov, M., Han, C., Baeg, G. H., Tan, Y., Zhang, Z., Lin, X., and He, X. (2002) Control of beta–catenin phosphorylation/degradation by a dual–kinase mechanism, Cell, 108, 837–847.CrossRefGoogle Scholar
  12. 12.
    Angers, S., and Moon, R. T. (2009) Proximal events in Wnt signal transduction, Nat. Rev. Mol. Cell Biol., 10, 468–477.CrossRefGoogle Scholar
  13. 13.
    Cadigan, K. M., and Waterman, M. L. (2012) TCF/LEFs and Wnt signaling in the nucleus, Cold Spring Harb. Perspect. Biol., 4, a007906.CrossRefGoogle Scholar
  14. 14.
    Pate, K. T., Stringari, C., Sprowl–Tanio, S., Wang, K., TeSlaa, T., Hoverter, N. P., McQuade, M. M., Garner, C., Digman, M. A., Teitell, M. A., Edwards, R. A., Gratton, E., and Waterman, M. L. (2014) Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer, EMBO J., 33, 1454–1473.Google Scholar
  15. 15.
    Yamada, T., Takaoka, A. S., Naishiro, Y., Hayashi, R., Maruyama, K., Maesawa, C., Ochiai, A., and Hirohashi, S. (2000) Transactivation of the multidrug resistance 1 gene by T–cell factor 4/beta–catenin complex in early colorectal carcinogenesis, Cancer Res., 60, 4761–4766.Google Scholar
  16. 16.
    Holland, J. D., Gyorffy, B., Vogel, R., Eckert, K., Valenti, G., Fang, L., Lohneis, P., Elezkurtaj, S., Ziebold, U., and Birchmeier, W. (2013) Combined Wnt/β–catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome, Cell Rep., 5, 1214–1227.Google Scholar
  17. 17.
    Nunez, F., Bravo, S., Cruzat, F., Montecino, M., and De Ferrari, G. V. (2011) Wnt/β–catenin signaling enhances cyclooxygenase–2 (COX2) transcriptional activity in gastric cancer cells, PLoS One, 6, e18562.CrossRefGoogle Scholar
  18. 18.
    Choe, Y., and Pleasure, S. J. (2012) Wnt signaling regulates intermediate precursor production in the postnatal dentate gyrus by regulating CXCR4 expression, Dev. Neurosci., 34, 502–514.CrossRefGoogle Scholar
  19. 19.
    Luis, T. C., Ichii, M., Brugman, M. H., Kincade, P., and Staal, F. J. (2012) Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development, Leukemia, 26, 414–421.CrossRefGoogle Scholar
  20. 20.
    Takada, S., Stark, K. L., Shea, M. J., Vassileva, G., McMahon, J. A., and McMahon, A. P. (1994) Wnt–3a regulates somite and tailbud formation in the mouse embryo, Genes Dev., 8, 174–189.CrossRefGoogle Scholar
  21. 21.
    Luis, T. C., Weerkamp, F., Naber, B. A., Baert, M. R., de Haas, E. F., Nikolic, T., Heuvelmans, S., De Krijger, R. R., van Dongen, J. J., and Staal, F. J. (2009) Wnt3a deficiency irreversibly impairs hematopoietic stem cell self–renewal and leads to defects in progenitor cell differentiation, Blood, 113, 546–554.CrossRefGoogle Scholar
  22. 22.
    Schraufstatter, I., Serobyan, N., DiScipio, R., Feofanova, N., Orlovskaya, I., and Khaldoyanidi, S. (2009) Hyaluronan stimulates mobilization of mature hematopoietic cells but not hematopoietic progenitors, J. Stem Cells, 4, 191–202.Google Scholar
  23. 23.
    Shirvaikar, N., Marquez–Curtis, L. A., and Janowska–Wieczorek, A. (2012) Hematopoietic stem cell mobilization and homing after transplantation: the role of MMP–2, MMP–9, and MT1–MMP, Biochem. Res. Int., 2012, 685267.Google Scholar
  24. 24.
    Calvi, L. M., Adams, G. B., Weibrecht, K. W., Weber, J. M., Olson, D. P., Knight, M. C., Martin, R. P., Schipani, E., Divieti, P., Bringhurst, F. R., Milner, L. A., Kronenberg, H. M., and Scadden, D. T. (2003) Osteoblastic cells regulate the haematopoietic stem cell niche, Nature, 425, 841–846.CrossRefGoogle Scholar
  25. 25.
    Kato, M., Patel, M. S., Levasseur, R., Lobov, I., Chang, B. H., Glass, D. A., Hartmann, C., Li, L., Hwang, T. H., Brayton, C. F., Lang, R. A., Karsenty, G., and Chan, L. (2002) Cbfa1–independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor, J. Cell Biol., 157, 303–314.Google Scholar
  26. 26.
    Abed, E., Chan, T. F., Delalandre, A., Martel–Pelletier, J., Pelletier, J. P., and Lajeunesse, D. (2011) R–spondins are newly recognized players in osteoarthritis that regulate Wnt signaling in osteoblasts, Arthritis Rheum., 63, 3865–3875.CrossRefGoogle Scholar
  27. 27.
    Pennetier, D., Oyallon, J., Morin–Poulard, I., Dejean, S., Vincent, A., and Crozatier, M. (2012) Size control of the Drosophila hematopoietic niche by bone morphogenetic protein signaling reveals parallels with mammals, Proc. Natl. Acad. Sci. USA, 109, 3389–3394.CrossRefGoogle Scholar
  28. 28.
    Yamane, T., Kunisada, T., Tsukamoto, H., Yamazaki, H., Niwa, H., Takada, S., and Hayashi, S. I. (2001) Wnt signaling regulates hemopoiesis through stromal cells, J. Immunol., 167, 765–772.CrossRefGoogle Scholar
  29. 29.
    Luis, T. C., Naber, B. A., Roozen, P. P., Brugman, M. H., de Haas, E. F., Ghazvini, M., Fibbe, W. E., van Dongen, J. J., Fodde, R., and Staal, F. J. (2011) Canonical Wnt signaling regulates hematopoiesis in a dosage–dependent fashion, Cell Stem Cell, 9, 345–356.CrossRefGoogle Scholar
  30. 30.
    Famili, F., Brugman, M. H., Taskesen, E., Naber, E. A., Fodde, R., and Staal, J. T. (2016) High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells, Stem Cell Rep., 6, 652–659.CrossRefGoogle Scholar
  31. 31.
    Schilham, M. W., Wilson, A., Moerer, P., Benaissa–Trouw, B. J., Cumano, A., and Clevers, H. C. (1998) Critical involvement of Tcf–1 in expansion of thymocytes, J. Immunol., 161, 3984–3991.Google Scholar
  32. 32.
    Gounari, F., Aifantis, I., Khazaie, K., Hoeflinger, S., Harada, N., Taketo, M. M., and von Boehmer, H. (2001) Somatic activation of beta–catenin bypasses pre–TCR signaling and TCR selection in thymocyte development, Nat. Immunol., 2, 863–869.CrossRefGoogle Scholar
  33. 33.
    Reya, T., O’Riordan, M., Okamura, R., Devaney, E., Willert, K., Nusse, R., and Grosschedl, R. (2000) Wnt signaling regulates B lymphocyte proliferation through a LEF–1 dependent mechanism, Immunity, 13, 15–24.CrossRefGoogle Scholar
  34. 34.
    Ranheim, E. A., Kwan, H. C., Reya, T., Wang, Y. K., Weissman, I. L., and Francke, U. (2005) Frizzled 9 knockout mice have abnormal B–cell development, Blood, 105, 2487–2494.CrossRefGoogle Scholar
  35. 35.
    Tarafdar, A., Dobbin, E., Corrigan, P., Freeburn, R., and Wheadon, H. (2013) Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation, PLoS One, 8, e81030.CrossRefGoogle Scholar
  36. 36.
    Paluru, P., Hudock, K. M., Cheng, X., Mills, J. A., Ying, L., Galvao, A. M., Lu, L., Tiyaboonchai, A., Sim, X., Sullivan, S. K., French, D. L., and Gadue, P. (2014) The negative impact of Wnt signaling on megakaryocyte and primitive erythroid progenitors derived from human embryonic stem cells, Stem Cell Res., 12, 441–451.CrossRefGoogle Scholar
  37. 37.
    Macaulay, I. C., Thon, J. N., Tijssen, M. R., Steele, B. M., MacDonald, B. T., Meade, G., Burns, P., Rendon, A., Salunkhe, V., Murphy, R. P., Bennett, C., Watkins, N. A., He, X., Fitzgerald, D. J., Italiano, J. E., and Maguire, P. B. (2013) Canonical Wnt signaling in megakaryocytes regulates proplatelet formation, Blood, 121, 188–196.CrossRefGoogle Scholar
  38. 38.
    Aoyama, K., Delaney, C., Varnum–Finney, B., Kohn, A. D., Moon, R. T., and Bernstein, I. D. (2007) The interaction of the Wnt and Notch pathways modulates natural killer versus T cell differentiation, Stem Cells, 25, 2488–2497.CrossRefGoogle Scholar
  39. 39.
    Muller–Tidow, C., Steffen, B., Cauvet, T., Tickenbrock, L., Ji, P., Diederichs, S., Sargin, B., Kohler, G., Stelljes, M., Puccetti, E., Ruthardt, M., de Vos, S., Hiebert, S. W., Koeffler, H. P., Berdel, W. E., and Serve, H. (2004) Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells, Mol. Cell Biol., 24, 2890–2904.CrossRefGoogle Scholar
  40. 40.
    Morgan, R. G., Pearn, L., Liddiard, K., Pumford, S. L., Burnett, A. K., Tonks, A., and Darley, R. L. (2013) γ–Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β–catenin, Leukemia, 27, 336–343.CrossRefGoogle Scholar
  41. 41.
    Simon, M., Grandage, V. L., Linch, D. C., and Khwaja, A. (2005) Constitutive activation of the Wnt/beta–catenin signaling pathway in acute myeloid leukemia, Oncogene, 24, 2410–2420.CrossRefGoogle Scholar
  42. 42.
    Ysebaert, L., Chicanne, G., Demur, C., De Toni, F., Prade–Houdellier, N., Ruidavets, J. B., Mansat–De Mas, V., Rigal–Huguet, F., Laurent, G., Payrastre, B., Manenti, S., and Racaud–Sultan, C. (2006) Expression of beta–catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis, Leukemia, 20, 1211–1216.CrossRefGoogle Scholar
  43. 43.
    Xu, J., Suzuki, M., Niwa, Y., Hiraga, J., Nagasaka, T., Ito, M., Nakamura, S., Tomita, A., Abe, A., Kiyoi, H., Kinoshita, T., and Naoe, T. (2008) Clinical significance of nuclear non–phosphorylated beta–catenin in acute myeloid leukemia and myelodysplastic syndrome, Br. J. Haematol., 140, 394–401.CrossRefGoogle Scholar
  44. 44.
    Tickenbrock, L., Hehn, S., Sargin, B., Choudhary, C., Baumer, N., Buerger, H., Schulte, B., Muller, O., Berdel, W. E., Muller–Tidow, C., and Serve, H. (2008) Activation of Wnt signaling in acute myeloid leukemia by induction of Frizzled–4, Int. J. Oncol., 33, 1215–1221.Google Scholar
  45. 45.
    Fu, Y., Zhu, H., Wu, W., Xu, J., Chen, T., Xu, B., Qian, S., Li, J., and Liu, P. (2014) Clinical significance of lymphoid enhancer–binding factor 1 expression in acute myeloid leukemia, Leuk. Lymphoma, 55, 371–377.CrossRefGoogle Scholar
  46. 46.
    Jost, E., Schmid, J., Wilop, S., Schubert, C., Suzuki, H., Herman, J. G., Osieka, R., and Galm, O. (2008) Epigenetic inactivation of secreted Frizzled–related proteins in acute myeloid leukemia, Br. J. Haematol., 142, 745–753.CrossRefGoogle Scholar
  47. 47.
    Valencia, A., Roman–Gomez, J., Cervera, J., Such, E., Barragan, E., Bolufer, P., Moscardo, F., Sanz, G. F., and Sanz, M. A. (2009) Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia, Leukemia, 23, 1658–1666.CrossRefGoogle Scholar
  48. 48.
    Guo, H., Zhang, T. J., Wen, X. M., Zhou, J. D., Ma, J. C., An, C., Zhang, W., Xu, Z. J., Lin, J., and Qian, J. (2017) Hypermethylation of secreted frizzled–related proteins predicts poor prognosis in non–M3 acute myeloid leukemia, Onco Targets Ther., 10, 3635–3644.CrossRefGoogle Scholar
  49. 49.
    Liang, H., Chen, Q., Coles, A. H., Anderson, S. J., Pihan, G., Bradley, A., Gerstein, R., Jurecic, R., and Jones, S. N. (2003) Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue, Cancer Cell, 4, 349–360.CrossRefGoogle Scholar
  50. 50.
    Griffiths, E. A., Gore, S. D., Hooker, C., McDevitt, M. A., Karp, J. E., Smith, B. D., Mohammad, H. P., Ye, Y., Herman, J. G., and Carraway, H. E. (2010) Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation, Leuk. Lymphoma, 51, 1711–1719.CrossRefGoogle Scholar
  51. 51.
    Fan, R., Zhang, L. Y., Wang, H., Yang, B., Han, T., Zhao, X. L., Wang, W., Wang, X. Q., and Lin, G. W. (2012) Methylation of the CpG island near SOX7 gene promoter is correlated with the poor prognosis of patients with myelodysplastic syndrome, Tohoku J. Exp. Med., 227, 119–128.CrossRefGoogle Scholar
  52. 52.
    Man, C. H., Fung, T. K., Wan, H., Cher, C. Y., Fan, A., Ng, N., Ho, C., Wan, T. S., Tanaka, T., So, C. W., Kwong, Y. L., and Leung, A. Y. (2015) Suppression of SOX7 by DNA methylation and its tumor suppressor function in acute myeloid leukemia, Blood, 125, 3928–3936.CrossRefGoogle Scholar
  53. 53.
    Kuhnl, A., Valk, P. J., Sanders, M. A., Ivey, A., Hills, R. K., Mills, K. I., Gale, R. E., Kaiser, M. F., Dillon, R., Joannides, M., Gilkes, A., Haferlach, T., Schnittger, S., Duprez, E., Linch, D. C., Delwel, R., Lowenberg, B., Baldus, C. D., Solomon, E., Burnett, A. K., and Grimwade, D. (2015) Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia, Blood, 125, 2985–2994.CrossRefGoogle Scholar
  54. 54.
    Yeung, J., Esposito, M. T., Gandillet, A., Zeisig, B. B., Griessinger, E., Bonnet, D., and So, C. W. (2010) β–Catenin mediates the establishment and drug resistance of MLL leukemic stem cells, Cancer Cell, 18, 606–618.CrossRefGoogle Scholar
  55. 55.
    Wang, Y., Krivtsov, A. V., Sinha, A. U., North, T. E., Goessling, W., Feng, Z., Zon, L. I., and Armstrong, S. A. (2010) The Wnt/beta–catenin pathway is required for the development of leukemia stem cells in AML, Science, 327, 1650–1653.CrossRefGoogle Scholar
  56. 56.
    Ma, S., Yang, L. L., Niu, T., Cheng, C., Zhong, L., Zheng, M. W., Xiong, Y., Li, L. L., Xiang, R., Chen, L. J., Zhou, Q., Wei, Y. Q., and Yang, S. Y. (2015) SKLB–677, an FLT3 and Wnt/β–catenin signaling inhibitor, displays potent activity in models of FLT3–driven AML, Sci. Rep., 5, 15646.Google Scholar
  57. 57.
    Fiskus, W., Sharma, S., Saha, S., Shah, B., Devaraj, S. G., Sun, B., Horrigan, S., Leveque, C., Zu, Y., Iyer, S., and Bhalla, K. N. (2015) Preclinical efficacy of combined therapy with novel β–catenin antagonist BC2059 and histone deacety–lase inhibitor against AML cells, Leukemia, 29, 1267–1278.CrossRefGoogle Scholar
  58. 58.
    Coluccia, M. L., Vacca, A., Dunach, M., Mologni, L., Redaelli, S., Bustos, V. H., Benati, D., Pinna, L. A., and Gambacorti–Passerini, C. (2007) Bcr–Abl stabilizes β–catenin in chronic myeloid leukemia through its tyrosine phosphorylation, EMBO J., 26, 1456–1466.CrossRefGoogle Scholar
  59. 59.
    Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., Sawyers, C. L., and Weissman, I. L. (2004) Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast–crisis CML, N. Engl. J. Med., 351, 657–667.CrossRefGoogle Scholar
  60. 60.
    Zhao, C., Blum, J., Chen, A., Kwon, H. Y., Jung, S. H., Cook, J. M., Lagoo, A., and Reya, T. (2007) Loss of beta–catenin impairs the renewal of normal and CML stem cells in vivo, Cancer Cell, 12, 528–541.CrossRefGoogle Scholar
  61. 61.
    Abrahamsson, A. E., Geron, I., Gotlib, J., Dao, K. H., Barroga, C. F., Newton, I. G., Giles, F. J., Durocher, J., Creusot, R. S., Karimi, M., Jones, C., Zehnder, J. L., Keating, A., Negrin, R. S., Weissman, I. L., and Jamieson, C. H. (2009) Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation, Proc. Natl. Acad. Sci. USA, 106, 3925–3929.CrossRefGoogle Scholar
  62. 62.
    Pehlivan, M., Caliskan, C., Yuce, Z., and Sercan, H. O. (2017) Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors, Tumour Biol., 39, 1010428317701654.CrossRefGoogle Scholar
  63. 63.
    Uhm, K. O., Lee, E. S., Lee, Y. M., Park, J. S., Kim, S. J., Kim, B. S., Kim, H. S., and Park, S. H. (2009) Differential methylation pattern of ID4, SFRP1, and SHP1 between acute myeloid leukemia and chronic myeloid leukemia, J. Korean Med. Sci., 24, 493–497.Google Scholar
  64. 64.
    Quintas–Cardama, A., Kantarjian, H. M., and Cortes, J. E. (2009) Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia, Cancer Control, 16, 122–131.CrossRefGoogle Scholar
  65. 65.
    Heidel, F. H., Bullinger, L., Feng, Z., Wang, Z., Neff, T. A., Stein, L., Kalaitzidis, D., Lane, S. W., and Armstrong, S. A. (2012) Genetic and pharmacologic inhibition of β–catenin targets imatinib–resistant leukemia stem cells in CML, Cell Stem Cell, 10, 412–424.CrossRefGoogle Scholar
  66. 66.
    Pehlivan, M., Sercan, Z., and Sercan, H. O. (2009) sFRP1 promoter methylation is associated with persistent Philadelphia chromosome in chronic myeloid leukemia, Leuk. Res., 33, 1062–1067.CrossRefGoogle Scholar
  67. 67.
    Liu, N., Zang, S., Liu, Y., Wang, Y., Li, W., Liu, Q., Ji, M., Ma, D., and Ji, C. (2016) FZD7 regulates BMSCs–mediated protection of CML cells, Oncotarget, 7, 6175–6187.Google Scholar
  68. 68.
    Labialle, S., Gayet, L., Marthinet, E., Rigal, D., and Baggetto, L. G. (2002) Transcriptional regulators of the human multidrug resistance 1 gene: recent views, Biochem. Pharmacol., 64, 943–948.CrossRefGoogle Scholar
  69. 69.
    Correa, S., Binato, R., Du Rocher, B., Castelo–Branco, M. T., Pizzatti, L., and Abdelhay, E. (2012) Wnt/β–catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia, BMC Cancer, 12,303.CrossRefGoogle Scholar
  70. 70.
    Eadie, L. N., Hughes, T. P., and White, D. L. (2014) Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib, Clin. Pharmacol. Ther., 95, 294–306.CrossRefGoogle Scholar
  71. 71.
    Eadie, L. N., Dang, P., Saunders, V. A., Yeung, D. T., Osborn, M. P., Grigg, A. P., Hughes, T. P., and White, D. L. (2017) The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first–line imatinib treatment, Leukemia, 31, 75–82.CrossRefGoogle Scholar
  72. 72.
    Lu, D., Zhao, Y., Tawatao, R., Cottam, H. B., Sen, M., Leoni, L. M., Kipps, T. J., Corr, M., and Carson, D. A. (2004) Activation of the Wnt signaling pathway in chronic lymphocytic leukemia, Proc. Natl. Acad. Sci. USA, 101, 3118–3123.CrossRefGoogle Scholar
  73. 73.
    Kaucka, M., Plevova, K., Pavlova, S., Janovska, P., Mishra, A., Verner, J., Prochazkova, J., Krejci, P., Kotaskova, J., Ovesna, P., Tichy, B., Brychtova, Y., Doubek, M., Kozubik, A., Mayer, J., Pospisilova, S., and Bryja, V. (2013) The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B–lymphocyte migration, Cancer Res., 73, 1491–1501.CrossRefGoogle Scholar
  74. 74.
    Poppova, L., Janovska, P., Plevova, K., Radova, L., Plesingerova, H., Borsky, M., Kotaskova, J., Kantorova, B., Hlozkova, M., Figulova, J., Brychtova, Y., Machalova, M., Urik, M., Doubek, M., Kozubik, A., Pospisilova, S., Pavlova, S., and Bryja, V. (2016) Decreased WNT3 expression in chronic lymphocytic leukemia is a hallmark of disease progression and identifies patients with worse prognosis in the subgroup with mutated IGHV, Br. J. Haematol., 175, 851–859.CrossRefGoogle Scholar
  75. 75.
    Khan, A., Hojjat–Farsangi, M., Daneshmanesh, A. H., Hansson, L., Kokhaei, P., Osterborg, A., Mellstedt, H., and Moshfegh, A. (2016) Dishevelled proteins are significantly upregulated in chronic lymphocytic leukemia, Tumour Biol., 37, 11947–11957.CrossRefGoogle Scholar
  76. 76.
    Wang, L., Shalek, A. K., Lawrence, M., Ding, R., Gaublomme, J. T., Pochet, N., Stojanov, P., Sougnez, C., Shukla, S. A., Stevenson, K. E., Zhang, W., Wong, J., Sievers, Q. L., MacDonald, B. T., Vartanov, A. R., Goldstein, N. R., Neuberg, D., He, X., Lander, E., Hacohen, N., Regev, A., Getz, G., Brown, J. R., Park, H., and Wu, C. J. (2014) Somatic mutation as a mechanism of Wnt/β–catenin pathway activation in CLL, Blood, 124, 1089–1098.CrossRefGoogle Scholar
  77. 77.
    Rush, L. J., Raval, A., Funchain, P., Johnson, A. J., Smith, L., Lucas, D. M., Bembea, M., Liu, T. H., Heerema, N. A., Rassenti, L., Liyanarachchi, S., Davuluri, R., Byrd, J. C., and Plass, C. (2004) Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets, Cancer Res., 64, 2424–2433.CrossRefGoogle Scholar
  78. 78.
    Seeliger, B., Wilop, S., Osieka, R., Galm, O., and Jost, E. (2009) CpG island methylation patterns in chronic lymphocytic leukemia, Leuk. Lymphoma, 50, 419–426.CrossRefGoogle Scholar
  79. 79.
    Rahmatpanah, F. B., Carstens, S., Hooshmand, S. I., Welsh, E. C., Sjahputera, O., Taylor, K. H., Bennett, L. B., Shi, H., Davis, J. W., Arthur, G. L., Shanafelt, T. D., Kay, N. E., Wooldridge, J. E., and Caldwell, C. W. (2009) Large–scale analysis of DNA methylation in chronic lymphocytic leukemia, Epigenomics, 1, 39–61.CrossRefGoogle Scholar
  80. 80.
    Gutierrez, A., Tschumper, R. C., Wu, X., Shanafelt, T. D., Eckel–Passow, J., Huddleston, P. M., Slager, S. L., Kay, N. E., and Jelinek, D. F. (2010) LEF–1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B–cell lymphocytosis, Blood, 116, 2975–2983.CrossRefGoogle Scholar
  81. 81.
    Erdfelder, F., Hertweck, M., Filipovich, A., Uhrmacher, S., and Kreuzer, K. A. (2010) High lymphoid enhancer–binding factor–1 expression is associated with disease progression and poor prognosis in chronic lymphocytic leukemia, Hematol. Rep., 2, e3.CrossRefGoogle Scholar
  82. 82.
    Wu, W., Zhu, H., Fu, Y., Shen, W., Miao, K., Hong, M., Xu, W., Fan, L., Young, K. H., Liu, P., and Li, J. (2016) High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid, Oncotarget, 7, 21631–21643.Google Scholar
  83. 83.
    Ng, O. H., Erbilgin, Y., Firtina, S., Celkan, T., Karakas, Z., Aydogan, G., Turkkan, E., Yildirmak, Y., Timur, C., Zengin, E., van Dongen, J. M., Staal, J. T., Ozbek, U., and Sayitoglu, M. (2014) Deregulated WNT signaling in childhood T–cell acute lymphoblastic leukemia, Blood Cancer J., 4, e192.CrossRefGoogle Scholar
  84. 84.
    Guo, X., Zhang, R., Liu, J., Li, M., Song, C., Dovat, S., Li, J., and Ge, Z. (2015) Characterization of LEF1 high expression and novel mutations in adult acute lymphoblastic leukemia, PLoS One, 10, e0125429.CrossRefGoogle Scholar
  85. 85.
    Giambra, V., Gusscott, S., Gracias, D., Song, R., and Weng, A. P. (2016) Lef1 Is a critical mediator of Wnt/β–catenin signaling in T–cell acute lymphoblastic leukemia (T–ALL), Blood, 128, 5083.Google Scholar
  86. 86.
    Yu, S., Zhou, X., Steinke, F. C., Liu, C., Chen, S. C., Zagorodna, O., Jing, X., Yokota, Y., Meyerholz, D. K., Mullighan, C. G., Knudson, C. M., Zhao, D. M., and Xue, H. H. (2012) The TCF–1 and LEF–1 transcription factors have cooperative and opposing roles in T cell development and malignancy, Immunity, 37, 813–826.CrossRefGoogle Scholar
  87. 87.
    Ferrando, A. A. (2009) The role of NOTCH1 signaling in T–ALL, Hematology Am. Soc. Hematol. Educ. Program, 2009, 353–361.CrossRefGoogle Scholar
  88. 88.
    Gekas, C., D’Altri, T., Aligue, R., Gonzalez, J., Espinosa, L., and Bigas, A. (2016) β–Catenin is required for T–cell leukemia initiation and MYC transcription downstream of Notch1, Leukemia, 30, 2002–2010.CrossRefGoogle Scholar
  89. 89.
    Giambra, V., Jenkins, C. E., Lam, S. H., Hoofd, C., Belmonte, M., Wang, X., Gusscott, S., Gracias, D., and Weng, A. P. (2015) Leukemia stem cells in T–ALL require active Hif1a and Wnt signaling, Blood, 125, 3917–3927.CrossRefGoogle Scholar
  90. 90.
    Khan, N. I., Bradstock, K. F., and Bendall, L. J. (2007) Activation of Wnt/beta–catenin pathway mediates growth and survival in B–cell progenitor acute lymphoblastic leukemia, Br. J. Haematol., 138, 338–348.CrossRefGoogle Scholar
  91. 91.
    Roman–Gomez, J., Cordeu, L., Agirre, X., Jimenez–Velasco, A., Jose–Eneriz, E., Garate, L., Calasanz, M. J., Heiniger, A., Torres, A., and Prosper, F. (2007) Epigenetic regulation of Wnt–signaling pathway in acute lymphoblastic leukemia, Blood, 109, 3462–3469.CrossRefGoogle Scholar
  92. 92.
    Kuhnl, A., Gokbuget, N., Kaiser, M., Schlee, C., Stroux, A., Burmeister, T., Mochmann, L. H., Hoelzer, D., Hofmann, W. K., Thiel, E., and Baldus, C. D. (2011) Overexpression of LEF1 predicts unfavorable outcome in adult patients with B–precursor acute lymphoblastic leukemia, Blood, 118, 6362–6367.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • T. I. Fetisov
    • 1
  • E. A. Lesovaya
    • 1
    • 2
  • M. G. Yakubovskaya
    • 1
  • K. I. Kirsanov
    • 1
    • 3
  • G. A. Belitsky
    • 1
    Email author
  1. 1.Blokhin National Medical Research Center of OncologyMoscowRussia
  2. 2.Pavlov Ryazan State Medical UniversityRyazanRussia
  3. 3.Peoples’ Friendship University of RussiaMoscowRussia

Personalised recommendations