It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies. 1. Introduction 1.1. Treatment of Chronic Leukemia Chronic myeloid leukemia (CML) is a one of the myeloproliferative diseases and represents 15–20% of all adult leukemia types. Depending on clinical aspects and laboratory findings, CML can be divided in three phases. Typically CML begins in the chronic phase, and over several years it progresses to the accelerated phase and finally to the blast crisis. By the introduction of the bcr-abl tyrosine kinase inhibitor (TKI) imatinib and the second-generation TKIs dasatinib and nilotinib, the treatment of CML has been revolutionized. The overall survival rate of patients with CML has been clearly improved. Nevertheless, resistance and incompatibilities against TKIs are well known, and a molecular remission is difficult to achieve [1]. Curing patients with CML could only be achieved by performing allogeneic stem cell transplantation (ASCT). Chronic lymphocytic leukemia (CLL) belonging to the indolent B-non-Hodgkin lymphoma (B-NHL) is the most common leukemia in the adult. The treatment of CLL mainly depends on the clinical stage of the disease, which is determined by the Binet staging system (A–C). In the early stage a “watch and wait” strategy is recommended. In progress of CLL, various chemotherapeutical options are determined. The application of fludarabine, cyclophosphamide, and rituximab (FCR) is one of the treatment standards in the first-line therapy of CLL [2]. Further alternative therapeutic options, particularly in progress or relapse and under consideration of several clinical aspects, have been established. These include the application of bendamustin and rituximab (R-Benda), chlorambucil, and alemtuzumab [2]. Despite the progress made in developing effective chemotherapeutic regimes, CLL remains an incurable disease. The only curative approach in CLL represents the performance of ASCT. 1.2. Wnt/β-Catenin Signaling Pathway The Wingless-Int (Wnt) signaling pathway plays an essential role in embryogenesis and proliferation, survival, and differentiation of hematopoietic stem cells (HSCs) [3, 4]. It
References
[1]
Y. Hu, Y. Chen, L. Douglas, and S. Li, “β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia,” Leukemia, vol. 23, no. 1, pp. 109–116, 2009.
[2]
M. Hallek and N. Pflug, “State of the art treatment of chronic lymphocytic leukaemia,” Blood Reviews, vol. 25, no. 1, pp. 1–9, 2011.
[3]
B. T. MacDonald, K. Tamai, and X. He, “Wnt/β-catenin signaling: components, mechanisms, and diseases,” Developmental Cell, vol. 17, no. 1, pp. 9–26, 2009.
[4]
M. Wilusz and M. Majka, “Role of the Wnt/β-catenin network in regulating hematopoiesis,” Archivum Immunologiae et Therapiae Experimentalis, vol. 56, no. 4, pp. 257–266, 2008.
[5]
A. Filipovich, I. Gehrke, S. J. Poll-Wolbeck, and K. A. Kreuzer, “Physiological inhibitors of Wnt signaling,” European Journal of Haematology, vol. 86, no. 6, pp. 453–465, 2011.
[6]
W. J. Nelson and R. Nusse, “Convergence of Wnt, β-catenin, and cadherin pathways,” Science, vol. 303, no. 5663, pp. 1483–1487, 2004.
[7]
X. Gao, J. Wen, L. Zhang et al., “Dapper1 is a nucleocytoplasmic shuttling protein that negatively modulates Wnt signaling in the nucleus,” Journal of Biological Chemistry, vol. 283, no. 51, pp. 35679–35688, 2008.
[8]
A. Novak and S. Dedhar, “Signaling through β-catenin and Lef/Tcf,” Cellular and Molecular Life Sciences, vol. 56, no. 5-6, pp. 523–537, 1999.
[9]
T. Akiyama, “Wnt/β-catenin signaling,” Cytokine and Growth Factor Reviews, vol. 11, no. 4, pp. 273–282, 2000.
[10]
C. Sakanaka, T. Q. Sun, L. T. Williams et al., “New steps in the Wnt/β-catenin signal transduction pathway,” Recent Progress in Hormone Research, vol. 55, pp. 225–236, 2000.
[11]
E. Porfiri, B. Rubinfeld, I. Albert, K. Hovanes, M. Waterman, and P. Polakis, “Induction of a β-catenin-LEF-1 complex by wnt-1 and transforming mutants of β-catenin,” Oncogene, vol. 15, no. 23, pp. 2833–2839, 1997.
[12]
M. Asally and Y. Yoneda, “β-catenin can act as a nuclear import receptor for its partner transcription factor, lymphocyte enhancer factor-1 (lef-1),” Experimental Cell Research, vol. 308, no. 2, pp. 357–363, 2005.
[13]
E. M. Sampson, Z. K. Haque, M. C. Ku et al., “Negative regulation of the Wnt-β-catenin pathway by the transcriptional repressor HBP1,” EMBO Journal, vol. 20, no. 16, pp. 4500–4511, 2001.
[14]
S. Wang and K. A. Jones, “CK2 controls the recruitment of Wnt regulators to target genes in vivo,” Current Biology, vol. 16, no. 22, pp. 2239–2244, 2006.
[15]
T. Kramps, O. Peter, E. Brunner et al., “Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear β-catenin-TCF complex,” Cell, vol. 109, no. 1, pp. 47–60, 2002.
[16]
R. Hoffmans, R. St？deli, and K. Basler, “Pygopus and legless provide essential transcriptional coactivator functions to armadillo/β-catenin,” Current Biology, vol. 15, no. 13, pp. 1207–1211, 2005.
[17]
E. H. Jho, T. Zhang, C. Domon, C. K. Joo, J. N. Freund, and F. Costantini, “Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway,” Molecular and Cellular Biology, vol. 22, no. 4, pp. 1172–1183, 2002.
[18]
S. Mokhtarzada, C. Yu, A. Brickenden, and W. Y. Choy, “Structural characterization of partially disordered human Chibby: insights into its function in the Wnt-signaling pathway,” Biochemistry, vol. 50, no. 5, pp. 715–726, 2011.
[19]
K. I. Tago, T. Nakamura, M. Nishita et al., “Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting protein,” Genes and Development, vol. 14, no. 14, pp. 1741–1749, 2000.
[20]
J. R. Prosperi and K. H. Goss, “A Wnt-ow of opportunity: targeting the Wnt/β-catenin pathway in breast cancer,” Current Drug Targets, vol. 11, no. 9, pp. 1074–1088, 2010.
[21]
W. Lu, H. N. Tinsley, A. Keeton, Z. Qu, G. A. Piazza, and Y. Li, “Suppression of Wnt/β-catenin signaling inhibits prostate cancer cell proliferation,” European Journal of Pharmacology, vol. 602, no. 1, pp. 8–14, 2009.
[22]
W. Chen, M. Chen, and L. S. Barak, “Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 299, no. 2, pp. G293–G300, 2010.
[23]
X. Ge and X. Wang, “Role of Wnt canonical pathway in hematological malignancies,” Journal of Hematology and Oncology, vol. 3, article 33, 2010.
[24]
Y. X. Wang, J. H. Zhang, and Z. W. Gu, “Wnt/β-catenin signal pathway and malignant hematological disease —review,” Zhongguo Shi Yan Xue Ye Xue Za Zhi, vol. 17, no. 1, pp. 234–237, 2009.
[25]
I. Gehrke, R. K. Gandhirajan, and K. A. Kreuzer, “Targeting the WNT/β-catenin/TCF/LEF1 axis in solid and haematological cancers: multiplicity of therapeutic options,” European Journal of Cancer, vol. 45, no. 16, pp. 2759–2767, 2009.
[26]
M. Aoki, A. Hecht, U. Kruse, R. Kemler, and P. K. Vogt, “Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 1, pp. 139–144, 1999.
[27]
C. Zhao, J. Blum, A. Chen et al., “Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo,” Cancer Cell, vol. 12, no. 6, pp. 528–541, 2007.
[28]
F. J. Giles, D. J. DeAngelo, M. Baccarani et al., “Optimizing outcomes for patients with advanced disease in chronic myelogenous leukemia,” Seminars in Oncology, vol. 35, supplement 1, pp. S1–S17, 2008.
[29]
J. P. Radich, H. Dai, M. Mao et al., “Gene expression changes associated with progression and response in chronic myeloid leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 8, pp. 2794–2799, 2006.
[30]
D. Lu, J. X. Liu, T. Endo et al., “Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/β-catenin pathway,” PloS one, vol. 4, no. 12, p. e8294, 2009.
[31]
A. Filipovich, R. K. Gandhirajan, I. Gehrke, S. J. Poll-Wolbeck, and K. A. Kreuzer, “Evidence for non-functional Dickkopf-1 (DKK-1) signaling in chronic lymphocytic leukemia (CLL),” European Journal of Haematology, vol. 85, no. 4, pp. 309–313, 2010.
[32]
R. K. Gandhirajan, S. J. Poll-Wolbeck, I. Gehrke, and K. A. Kreuzer, “Wnt/β-catenin/LEF-1 signaling in chronic lymphocytic leukemia (CLL): a target for current and potential therapeutic options,” Current Cancer Drug Targets, vol. 10, no. 7, pp. 716–727, 2010.
[33]
A. Gutierrez Jr, R. C. Tschumper, X. Wu et al., “LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis,” Blood, vol. 116, no. 16, pp. 2975–2983, 2010.
[34]
L. B. Bennett, K. H. Taylor, G. L. Arthur, F. B. Rahmatpanah, S. I. Hooshmand, and C. W. Caldwell, “Epigenetic regulation of WNT signaling in chronic lymphocytic leukemia,” Epigenomics, vol. 2, no. 1, pp. 53–70, 2010.
[35]
D. Lu, Y. Zhao, R. Tawatao et al., “Activation of the Wnt signaling pathway in chronic lymphocytic leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 3118–3123, 2004.
[36]
H. Yao, E. Ashihara, and T. Maekawa, “Targeting the Wnt/β-catenin signaling pathway in human cancers,” Expert Opinion on Therapeutic Targets, vol. 15, no. 7, pp. 873–887, 2011.
[37]
J. C. Curtin and M. V. Lorenzi, “Drug discovery approaches to target Wnt signaling in cancer stem cells,” Oncotarget, vol. 1, no. 7, pp. 563–577, 2010.
[38]
A. J. Chien and R. T. Moon, “WNTS and WNT receptors as therapeutic tools and targets in human disease processes,” Frontiers in Bioscience, vol. 12, no. 2, pp. 448–457, 2007.
[39]
K. S. Minke, P. Staib, A. Puetter et al., “Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells,” European Journal of Haematology, vol. 82, no. 3, pp. 165–175, 2009.
[40]
Y. Kim, G. Reifenberger, D. Lu et al., “Influencing the Wnt signaling pathway in multiple myeloma,” Anticancer Research, vol. 31, no. 2, pp. 725–730, 2011.
[41]
K. Wang, Q. Ma, Y. Ren et al., “Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/β-catenin signaling in HER2 overexpressing human breast cancer cells,” Oncology Reports, vol. 17, no. 1, pp. 89–96, 2007.
[42]
G. Jin, D. Lu, S. Yao et al., “Amide derivatives of ethacrynic acid: synthesis and evaluation as antagonists of Wnt/β-catenin signaling and CLL cell survival,” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 3, pp. 606–609, 2009.
[43]
D. Lu, M. Y. Choi, J. Yu, J. E. Castro, T. J. Kipps, and D. A. Carson, “Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 32, pp. 13253–13257, 2011.
[44]
R. Razavi, I. Gehrke, R. K. Gandhirajan, S. J. Poll-Wolbeck, M. Hallek, and K. A. Kreuzer, “Nitric oxide-donating acetylsalicylic acid induces apoptosis in chronic lymphocytic leukemia cells and shows strong antitumor efficacy in vivo,” Clinical Cancer Research, vol. 17, no. 2, pp. 286–293, 2011.
[45]
R. K. Gandhirajan, P. A. Staib, K. Minke et al., “Small molecule inhibitors of Wnt/β-Catenin/Lef-1 Signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo,” Neoplasia, vol. 12, no. 4, pp. 326–335, 2010.
