Abstract
Wnt signaling plays an important role in stem cell self-renewal and proliferation. Aberrant activation of Wnt signaling and its downstream targets are intimately linked with several types of cancer with colon cancer being the best-studied example. However, recent results also suggest an important role of Wnt signaling in normal as well as leukemic hematopoietic stem cells. Aberrant activation of Wnt signaling and downstream effectors has been demonstrated in acute myeloid leukemia. Here, mutant receptor tyrosine kinases, such as Flt3 and chimeric transcription factors such as promyelocytic leukemia-retinoic acid receptor-α and acute myeloid leukemia1-ETO, induce downstream Wnt signaling events. These findings suggest that the Wnt signaling pathway is an important target in several leukemogenic pathways and may provide a novel opportunity for targeting leukemic stem cells.
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References
Steffen B, Müller-Tidow C, Schwäble J, Berdel W, Serve H . The molecular pathogenesis of acute myeloid leukemia. Crit Rev Oncol/Haematol 2005; 56: 195–221.
Jordan CT, Guzman ML, Noble M . Cancer stem cells. N Engl J Med 2006; 355: 1253–1261.
Bonnet D, Dick JE . Human acute leukemia is organized as a hierarchy that originates from a primitive haematopoietic cell. Nat Med 1997; 3: 730–737.
Huntly BJ, Gilliland DG . Blasts from the past: new lessons in stem cell biology from chronic myelogenous leukemia. Cancer Cell 2004; 6: 199–201.
Huntly BJ, Gilliland DG . Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 2005; 5: 311–321.
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.
Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.
Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine haematopoietic progenitors. Cancer Cell 2004; 6: 587–596.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–822.
Wang JC, Dick JE . Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005; 15: 494–501.
Guzman ML, Jordan CT . Considerations for targeting malignant stem cells in leukemia. Cancer Control 2004; 11: 97–104.
Dick JE . Acute myeloid leukemia stem cells. Ann NY Acad Sci 2005; 1044: 1–5.
Holyoake TL, Jiang X, Drummond MW, Eaves AC, Eaves CJ . Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia 2002; 16: 549–558.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature 1994; 367: 645–648.
Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH . Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3 specific inhibitor. Nat Med 2004; 10: 55–63.
Kielman MF, Rindapaa M, Gaspar C, van Poppel N, Breukel C, van Leeuwen S et al. Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling. Nat Genet 2002; 32: 594–605.
Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE . Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 1988; 55: 619–625.
Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science 1997; 275: 1752–1753.
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275: 1787–1790.
Pardal R, Clarke MF, Morrison SJ . Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3: 895–902.
Al-Hajj M, Clarke MF . Self-renewal and solid tumor stem cells. Oncogene 2004; 23: 7274–7282.
Reya T, Clevers H . Wnt signalling in stem cells and cancer. Nature 2005; 434: 843–850.
Austin TW, Solar GP, Ziegler FC, Liem L, Matthews WA . A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells. Blood 1997; 89: 3624–3635.
Brandon C, Eisenberg LM, Eisenberg CA . Wnt signaling modulates the diversification of haematopoietic cells. Blood 2000; 96: 4132–4141.
van Noort M, Clevers H . TCF transcription factors, mediators of Wnt-signaling in development and cancer. Dev Biol 2002; 244: 1–8.
Smalley MJ, Dale TC . Wnt signalling in mammalian development and cancer. Cancer Metast Rev 1999; 18: 215–230.
Malbon CC . Frizzleds: new members of the superfamily of G-protein-coupled receptors. Front Biosci 2004; 9: 1048–1058.
Wang HY . Wnt-frizzled signaling via cyclic GMP. Front Biosci 2004; 9: 1043–1047.
Kuhl M . The WNT/calcium pathway: biochemical mediators, tools and future requirements. Front Biosci 2004; 9: 967–974.
Clevers H . Wnt breakers in colon cancer. Cancer Cell 2004; 5: 5–6.
Wang HY, Malbon CC . Wnt-frizzled signaling to G-protein-coupled effectors. Cell Mol Life Sci 2004; 61: 69–75.
Veeman MT, Axelrod JD, Moon RT . A second canon. Functions and mechanisms of β-catenin independent Wnt signaling. Dev Cell 2003; 5: 367–377.
Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC . An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 2000; 407: 535–538.
Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 2000; 407: 530–535.
Mao J, Wang J, Liu B, Pan W, Farr III GH, Flynn C et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 2001; 7: 801–809.
Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A et al. Niehrs C. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 2001; 411: 321–325.
Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R et al. Functional interaction of an axin homolog, conductin, with β-catenin, APC, and GSK3β. Science 1998; 280: 596–599.
Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A . Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK- 3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J 1998; 17: 1371–1384.
Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P . Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 1998; 8: 573–581.
Peters JM, McKay RM, McKay JP, Graff JM . Casein kinase I transduces Wnt signals. Nature 1999; 401: 345–350.
Sakanaka C, Leong P, Xu L, Harrison SD, Williams LT . Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin function. Proc Natl Acad Sci USA 1999; 96: 12548–12552.
Polakis P . Casein kinase 1: a Wnt'er of disconnect. Curr Biol 2002; 12: R499–R501.
Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M et al. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 2002; 16: 1066–1076.
Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002; 108: 837–847.
Yanagawa S, Matsuda Y, Lee JS, Matsubayashi H, Sese S, Kadowaki T et al. casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila. EMBO J 2002; 21: 1733–1742.
Vancura A, Sessler A, Leichus B, Kuret J . A prenylation motif is required for plasma membrane localization and biochemical function of casein kinase I in budding yeast. J Biol Chem 1994; 269: 19271–19278.
Gietzen KF, Virshup DM . Identification of inhibitory autophosphorylation sites in casein kinase I epsilon. J Biol Chem 1999; 274: 32063–32070.
Cegielska A, Gietzen KF, Rivers A, Virshup DM . Autoinhibition of casein kinase I epsilon (CKI epsilon) is relieved by protein phosphatases and limited proteolysis. J Biol Chem 1998; 273: 1357–1364.
Rivers A, Gietzen KF, Vielhaber E, Virshup DM . Regulation of casein kinase I epsilon and casein kinase I delta by an in vivo futile phosphorylation cycle. J Biol Chem 1998; 273: 15980–15984.
Karim R, Tse G, Putti T, Scolyer R, Lee S . The significance of the Wnt pathway in the pathology of human cancers. Pathology 2004; 36: 120–128.
Liu X, Rubin JS, Kimmel AR . Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins. Curr Biol 2005; 15: 1989–1997.
Seto ES, Bellen HJ . The ins and outs of Wingless signaling. Trend Cell Biol 2004; 14: 45–53.
Nelson WJ, Nusse R . Convergence of Wnt, β-catenin, and cadherin pathways. Science 2004; 303: 1483–1487.
van Es JH, Barker N, Clevers H . You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev 2003; 13: 28–33.
Eastman Q, Grosschedl R . Regulation of LEF1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol 1999; 11: 233–240.
Giles RH, van Es JH, Clevers H . Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1–24.
Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S et al. Wnt/wingless ignaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear β-catenin-TCF complex. Cell 2002; 109: 47–60.
Townsley FM, Thompson B, Bienz M . Pygopus residues required for its binding to Legless are critical for transcription and development. J Biol Chem 2004; 279: 5177–5183.
Townsley FM, Cliffe A, Bienz M . Pygopus and Legless target Armadillo/β-catenin to the nucleus to enable its transcriptional co-activator function. Nat Cell Biol 2004; 6: 626–633.
Thompson BJ . A complex of Armadillo, Legless, and Pygopus coactivates dTCF to activate wingless targets genes. Curr Biol 2004; 14: 458–466.
Daniels DL, Weis WI . ICAT inhibits β-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules. Mol Cell 2002; 10: 573–584.
Takemaru K, Yamaguchi S, Lee YS, Zhang Y, Carthew RW, Moon RT . Chibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway. Nature 2003; 422: 905–909.
Yan D, Wallingford JB, Sun TQ, Nelson AM, Sakanaka C, Reinhard C et al. Cell autonomous regulation of Dishevelled dependent pathways by mammalian Nkd. Proc Natl Acad Sci USA 2001; 98: 3802–3807.
Park M, Moon RT . The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos. Nat Cell Biol 2002; 4: 20–25.
Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH . Regulation of the Wnt signaling pathway by disabled-2 (Dab2). EMBO J 2003; 22: 3084–3094.
Xu XX, Yi T, Tang B, Lambeth JD . Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Oncogene 1998; 16: 1561–1569.
Hocevar BA, Smine A, Xu XX, Howe PH . The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J 2001; 20: 2789–2801.
Polakis P . Wnt signaling and cancer. Genes Dev 2000; 14: 1837–1851.
Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996; 382: 638–642.
Pelengaris S, Khan M, Evan GI . c-MYC: more than just a matter of life and death. Nat Rev Cancer 2002; 2: 764–776.
Ioannidis V, Beermann F, Clevers H, Held W . The β-catenin-TCF-1 pathway ensures CD4+CD8+ thymocyte survival. Nat Immunol 2001; 2: 691–697.
Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci USA 2003; 100: 3422–3427.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409–414.
Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003; 423: 448–452.
Staal FJT, Clevers HC . Wnt signaling and haematopoiesis: a wnt–wnt situation. Nat Rev Immunol 2005; 5: 21–30.
Zheng X, Beissert T, Kukoc-Zivojnov N, Puccetti E, Altschmied J, Strolz C et al. Gamma-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells. Blood 2004; 103: 3534–3543.
van den Berg DJ, Sharma AK, Bruno E, Hoffman R . Role of members of the Wnt gene family in human haematopoiesis. Blood 1998; 89: 3189–3202.
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003; 425: 841–846.
Zhang J, Niu C, Ye L, Huang H, He X, Tong WG et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003; 425: 836–841.
Rattis FM, Voermans C, Reya T . Wnt signaling in the stem cell niche. Curr Opin Hematol 2004; 11: 88–94.
Reya T, O'Riordan M, Okamura R, Devaney E, Willert K, Nusse R et al. Wnt signalling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity 2000; 13: 15–24.
Hackney JA, Charbord P, Brunk BP, Stoeckert CJ, Lemischka IR, Moore KA . A molecular profile of a hematopoietic stem cell niche. Proc Natl Acad Sci USA 2002; 99: 13061–13066.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD . Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.
Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT . Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 2001; 294: 2542–2545.
Moore KA . Recent advances in defining the haematopoietic stem cell niche. Curr Opin Haematol 2004; 11: 107–111.
Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001; 2: 172–180.
Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 2000; 6: 1278–1281.
Hing HK, Sun X, Artavanis-Tsakonas S . Modulation of wingless signaling by Notch in Drosophila. Mech Dev 1994; 47: 261–268.
Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C et al. Integration of Notch and Wnt signaling in haematopoietic stem cell maintenance. Nat Immunol 2005; 6: 314–322.
Radtke F, Raj K . The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 2003; 3: 756–767.
Kirstetter P, Anderson K, Porse BT, Jacobsen SEW, Nerlov C . Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 2006; 7: 1048–1056.
Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nat Immunol 2006; 7: 1037–1047.
Müller-Tidow C, Steffen B, Cuavet T, Tickenbrock L, Ji P, Diederichs S et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in haematopoietic cells. Mol Cell Biol 2004; 24: 2890–2904.
Zhurinsky J, Shtutman M, Ben-Ze'ev A . Plakoglobin and beta-catenin: protein interactions, regulation and biological roles. J Cell Sci 2000; 113: 3127–3139.
Kolligs FT, Kolligs B, Hajra KM, Hu G, Tani M, Cho KR et al. gamma-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin. Genes Dev 2000; 14: 1319–1331.
Mulloy JC, Cammenga J, Mac Kenzie KL, Berguido FJ, Moore MA, Nimer SD . The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood 2002; 99: 15–23.
Tonks A, Pearn L, Tonks AJ, Pearce L, Hoy T, Phillips S et al. The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells. Blood 2003; 101: 624–632.
Kawano Y, Kypta R . Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003; 116: 2627–2634.
Chim CS, Liang R, Tam C, Kwong YL . P15 and P16 promoter methylation in acute promyelocytic leukemia. J Clin Oncol 2001; 19: 2033–2040.
Chim CS, Liang R, Kwong YL . Gene promoter hypermethylation in hematologic malignancies. Hematol Oncol 2002; 20: 167–176.
Agrawal S, Hofmann WK, Tidow N, Ehrich M, van den Boom D, Koschmieder S et al. The C/EBP{delta} tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood 2007; 9: 3895–3905.
Agrawal S, Unterberg M, Koschmieder S, Zur Stadt U, Brunnberg U, Verbeek W et al. DNA methylation of tumor suppressor genes in clinical remission predicts the relapse risk in acute myeloid leukaemia. Cancer Res 2007; 67: 1370–1377.
Chim CS, Chan WWL, Pang A, Kwong YL . Preferential methylation of Wnt inhibitory factor-1 in acute promyelocytic leukemia: an independent poor prognostic factor. Leukemia 2006; 20: 907–909.
Gilliland DG, Griffin JD . The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.
Zhao M, Kiyoi H, Yamamoto Y, Ito M, Towatari M, Omura S et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 2000; 14: 374–378.
Levis M, Tse KF, Smith BD, Garrett E, Small D . A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 2001; 98: 885–887.
Tse KF, Mukherjee G, Small D . Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia 2000; 14: 1766–1776.
Mizuki M, Schwäble J, Steur C, Choudhary C, Agrawal S, Sargin B et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 2003; 101: 3164–3173.
Tickenbrock L, Schwäble J, Wiedehage M, Steffen B, Sargin B, Choudhary C et al. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood 2005; 105: 3699–3706.
Simon M, Grandage VL, Linch DC, Khwaja A . Constitutive activation of the Wnt/β-catenin signalling pathway in acute myeloid leukemia. Oncogene 2005; 24: 2410–2420.
Fukumoto S, Hsieh CM, Maemura K, Layne MD, Yet SF, Lee KH . Akt participation in the Wnt signaling pathway through Dishevelled. J Biol Chem 2001; 276: 17479–17483.
Sharma M, Chuang WW, Sun Z . Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem 2002; 277: 30935–30941.
Kubota Y, Ohnishi H, Kitanaka A, Ishida T, Tanaka T . Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: direct evidence of PI3K activation. Leukemia 2004; 18: 1438–1440.
Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukaemia: its significance as a prognostic variable. Leukemia 2003; 17: 995–997.
Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M . Survival of acute myeloid leucemia cells requires PI3 kinase activation. Blood 2003; 102: 972–980.
Zhao S, Konopleva M, Cabreira-Hansen M, Xie Z, Hu W, Milella M et al. Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. Leukemia 2004; 18: 267–275.
Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwäble J et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005; 65: 9643–9650.
Li FQ, Person RE, Takemaru KI, Williams K, Meade-White K, Ozsahin AH et al. Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. J Biol Chem 2004; 279: 2873–2884.
Skokowa J, Cario G, Uenalan M, Schambach A, Germeshausen M, Battmer K et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med 2006; 12: 1191–1197.
Serinsoz E, Neusch M, Busche G, Wasielewski R, Kreipe H, Bock O . Aberrant expression of beta-catenin discriminates acute myeloid leukaemia from acute lymphoblastic leukaemia. Br J Haematol 2004; 126: 313–319.
Ysebaert L, Chicanne G, Demur C, De Toni F, Prade-Houdellier N, Ruidavets JB et al. Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia 2006; 20: 1211–1216.
Bafico A, Liu G, Goldin L, Harris V, Aaronson SA . An autocrine mechanism of constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004; 6: 497–506.
Mc Whirter JR, Neuteboom ST, Wancewicz EV, Monia BP, Downing JR, Murre C . Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel Wnt gene in pre-B acute lymphoblastoid leukemia. Proc Natl Acad Sci 1999; 96: 11464–11469.
Derksen PW, Tijn E, Meijer H, Klok MD, MacGillavry MH, van Oers MH et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Aca Sci USA 2004; 24: 2890–2904.
Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM et al. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood 2006; 108: 2726–2735.
Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 2002; 71: 1195–1199.
Ma Y, Li D, Chai L, Luciani AM, Ford D, Morgan J et al. Cloning and characterization of two promoters for the human HSAL2 gene and their transcriptional repression by the Wilms tumor suppressor gene product. J Biol Chem 2001; 276: 48223–48230.
Ma Y, Singer DB, Gozman A, Ford D, Chai L, Steinhoff MM et al. Hsal 1 is related to kidney and gonad development and is expressed in Wilms tumor. Pediatr Nephrol 2001; 16: 701–709.
Ma Y, Chai L, Cortez SC, Stopa EG, Steinhoff MM, Ford D et al. SALL1 expression in the human pituitary-adrenal/gonadal axis. J Endocrinol 2002; 173: 437–448.
Marlin S, Blanchard S, Slim R, Lacombe D, Denoyelle F, Alessandri JL et al. Townes–Brocks syndrome: detection of a SALL1 mutation hot spot and evidence for a position effect in one patient. Hum Mutat 1999; 14: 377–386.
Nishinakamura R, Matsumoto Y, Nakao K, Nakamura K, Sato A, Copeland NG et al. Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development 2001; 128: 3105–3115.
Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN et al. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J Med Genet 2003; 40: 473–478.
Bohm J, Sustmann C, Wilhelm C, Kohlhase J . SALL4 is directly activated by TCF/LEF in the canonical Wnt signaling pathway. Biochem Biophys Res Commun 2006; 348: 898–907.
Ross SE, Hemati N, Lomgo KA, Bennett CN, Lucas PC, Erickson RL et al. Inhibition of adipogenesis by Wnt signaling. Science 2000; 289: 950–953.
Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med 2001; 7: 444–451.
Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG . CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998; 18: 4301–4314.
Tenen DG . Abnormalities of the CEBP alpha transcription factor: a major target in acute myeloid leukemia. Leukemia 2001; 15: 688–689.
Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG . Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 1997; 94: 569–574.
Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 2003; 4: 349–360.
Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan BJ, Yang Y . Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. J Cell Biol 2003; 162: 899–908.
de Toni F, Racaud-Sultan C, Chicanne G, Mansat-De Mas V, Cariven C, Mesange F et al. A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukaemia. Oncogene 2006; 25: 3113–3122.
Tickenbrock L, Schwäble J, Strey A, Sargin B, Hehn S, Baas M et al. Wnt signaling regulates transendothelial migration of monocytes. J Leukoc Biol 2005; 79: 1306–1311.
Kim SE, Lee WJ, Choi KY . The PI3 kinase-Akt pathway mediates Wnt3a-induced proliferation. Cell Signal 2007; 19: 511–518.
Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 2007; 67: 684–694.
Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW et al. Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol 2003; 122: 454–456.
Grandage VL, Gale RE, Linch DC, Khwaja A . PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistence via NF-kappaB, Mapkinase and p53 pathways. Leukemia 2005; 19: 586–594.
Weerkamp F, van Dongen JJM, Staal FJT . Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia. Leukemia 2006; 20: 1197–1205.
Weng AP, Ferrando AA, Lee W, Morris IV JP, Silverman LB, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.
Beverly LJ, Felsher DW, Capobianco AJ . Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression. Cancer Res 2005; 65: 7159–7168.
Vacca A, Felli MP, Palermo R, Di Mario G, Calce A, Di Giovine M et al. Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukaemia. EMBO J 2006; 25: 1000–1008.
Herbst A, Kolligs FT . Wnt signaling as a therapeutic target for cancer. Methods Mol Biol 2007; 361: 63–91.
Zhou L, An N, Haydon RC, Zhou O, Cheng H, Peng Y et al. Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity. Cancer Letters 2003; 25: 161–170.
You L, Kim J, He B, Xu Z, McCormick F, Jablons DM . Wnt-1 signal as a potential cancer therapeutic target. Drug News Perspect 2006; 19: 27–31.
Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB . Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer. Clin Cancer Res 2003; 9: 1291–1300.
Mazieres J, You L, He B, Xu Z, Lee AY, Mikami I et al. Inhibition of Wnt16 in human acute lymphoblastoid leukemia cells containing the t(1;19) translocation induces apoptosis. Oncogene 2005; 24: 5396–5400.
Acknowledgements
Research in our laboratory was funded by the Deutsche Forschungsgemeinschaft, Josè-Carreras Foundation, Deutsche Krebshilfe and the Interdisciplinary Center of Clinical Research at the University of Münster.
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Mikesch, JH., Steffen, B., Berdel, W. et al. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia 21, 1638–1647 (2007). https://doi.org/10.1038/sj.leu.2404732
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DOI: https://doi.org/10.1038/sj.leu.2404732
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