Abstract
The β-catenin protein is at the core of the canonical Wnt signalling pathway. Wnt stimulation leads to β-catenin accumulation, nuclear translocation and interaction with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to regulate genes important for embryonic development and proliferation. Wnt/β-catenin can promote stem cell self-renewal and is dysregulated in colon carcinoma. We have examined the role of the Wnt pathway in the development of acute myeloid leukaemia (AML) and find that the β-catenin protein is readily detected in primary AML samples. Using transfection of a TCF/LEF reporter construct into primary AML cells and normal human progenitors, we find increased reporter activity in 16/25 leukaemia samples. Retrovirally mediated expression of a mutant active β-catenin in normal progenitors preserves CD34 expression and impairs myelomonocytic differentiation. Activation of TCF/LEF signalling decreases factor withdrawal-induced apoptosis of normal progenitors. A significant proportion of AML cases show aberrant expression of components of the Wnt pathway including Wnt-1, Wnt-2b and LEF-1. These results provide evidence for the involvement of the Wnt/β-catenin pathway in the pathogenesis of AML.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT and Hruban RH . (2002). Am. J. Pathol., 160, 1361–1369.
Antonchuk J, Sauvageau G and Humphries RK . (2002). Cell, 109, 39–45.
Ardeshna KM, Pizzey AR, Devereux S and Khwaja A . (2000). Blood, 96, 1039–1046.
Austin TW, Solar GP, Ziegler FC, Liem L and Matthews W . (1997). Blood, 89, 3624–3635.
Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, van de Wetering M, Pawson T and Clevers H . (2002). Cell, 111, 251–263.
Bienz M and Clevers H . (2000). Cell, 103, 311–320.
Chung EJ, Hwang SG, Nguyen P, Lee S, Kim JS, Kim JW, Henkart PA, Bottaro DP, Soon L, Bonvini P, Lee SJ, Karp JE, Oh HJ, Rubin JS and Trepel JB . (2002). Blood, 100, 982–990.
Cobas M, Wilson A, Ernst B, Mancini SJ, MacDonald HR, Kemler R and Radtke F . (2004). J. Exp. Med, 199, 221–229.
Conacci-Sorrell M, Zhurinsky J and Ben-Ze'ev A . (2002). J. Clin. Invest., 109, 987–991.
Danilkovitch-Miagkova A, Miagkov A, Skeel A, Nakaigawa N, Zbar B and Leonard EJ . (2001). Mol. Cell. Biol., 21, 5857–5868.
Davies SP, Reddy H, Caivano M and Cohen P . (2000). Biochem. J., 351, 95–105.
Fagotto F, Jho E, Zeng L, Kurth T, Joos T, Kaufmann C and Costantini F . (1999). J. Cell Biol., 145, 741–756.
Giles RH, van Es JH and Clevers H . (2003). Biochim. Biophys. Acta, 1653, 1–24.
Huelsken J, Vogel R, Erdmann B, Cotsarelis G and Birchmeier W . (2001). Cell, 105, 533–545.
Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL and Weissman IL . (2004). N. Engl. J. Med., 351, 657–667.
Kelly LM and Gilliland DG . (2002). Annu. Rev. Genomics Hum. Genet., 3, 179–198.
Kelly PF, Vandergriff J, Nathwani A, Nienhuis AW and Vanin EF . (2000). Blood, 96, 1206–1214.
Kikuchi A . (2003). Cancer Sci., 94, 225–229.
Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H . (1997). Science, 275, 1784–1787.
Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH and Linch DC . (2001). Blood, 98, 1752–1759.
Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT and Linch DC . (2002). Blood, 100, 2393–2398.
Lai W, Chang CH and Farber DL . (2003). J. Immunol. Methods, 282, 93–102.
Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A, Gerstein R, Jurecic R and Jones SN . (2003). Cancer Cell, 4, 349–360.
McWhirter JR, Neuteboom ST, Wancewicz EV, Monia BP, Downing JR and Murre C . (1999). Proc. Natl. Acad. Sci. USA, 96, 11464–11469.
Moon RT, Bowerman B, Boutros M and Perrimon N . (2002). Science, 296, 1644–1646.
Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, Sargin B, Kohler G, Stelljes M, Puccetti E, Ruthardt M, deVos S, Hiebert SW, Koeffler HP, Berdel WE and Serve H . (2004). Mol. Cell. Biol., 24, 2890–2904.
Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, Moon RT and Bhatia M . (2003). Proc. Natl. Acad. Sci. USA, 100, 3422–3427.
Orford K, Crockett C, Jensen JP, Weissman AM and Byers SW . (1997). J. Biol. Chem., 272, 24735–24738.
Quentmeier H, Reinhardt J, Zaborski M and Drexler HG . (2003). Leukemia, 17, 120–124.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R and Weissman IL . (2003). Nature, 423, 409–414.
Reya T, Morrison SJ, Clarke MF and Weissman IL . (2001). Nature, 414, 105–111.
Reya T, O'Riordan M, Okamura R, Devaney E, Willert K, Nusse R and Grosschedl R . (2000). Immunity, 13, 15–24.
Smalley MJ and Dale TC . (1999). Cancer Metast. Rev., 18, 215–230.
Stier S, Cheng T, Dombkowski D, Carlesso N and Scadden DT . (2002). Blood, 99, 2369–2378.
Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan PJ and Yang Y . (2003). J. Cell Biol., 162, 899–908.
Trompeter HI, Weinhold S, Thiel C, Wernet P and Uhrberg M . (2003). J. Immunol. Methods, 274, 245–256.
Uematsu K, He B, You L, Xu Z, McCormick F and Jablons DM . (2003a). Oncogene, 22, 7218–7221.
Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K, Peterlin BM, McCormick F and Jablons DM . (2003b). Cancer Res., 63, 4547–4551.
van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R and Clevers H . (2002). Cell, 111, 241–250.
Van Den Berg DJ, Sharma AK, Bruno E and Hoffman R . (1998). Blood, 92, 3189–3202.
Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, Pear WS and Bernstein ID . (2000). Nat. Med., 6, 1278–1281.
Watts MJ, Somervaille TC, Ings SJ, Ahmed F, Khwaja A, Yong K and Linch DC . (2002). Br. J. Haematol., 118, 117–123.
Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates III JR and Nusse R . (2003). Nature, 423, 448–452.
Zheng X, Beissert T, Kukoc-Zivojnov N, Puccetti E, Altschmied J, Strolz C, Boehrer S, Gul H, Schneider O, Ottmann OG, Hoelzer D, Henschler R and Ruthardt M . (2004). Blood, 103, 3535–3543.
Acknowledgements
MS was supported by Leukaemia Research, UK, VLG by the Kay Kendall Leukaemia Fund and AK by the Medical Research Council, UK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Simon, M., Grandage, V., Linch, D. et al. Constitutive activation of the Wnt/β-catenin signalling pathway in acute myeloid leukaemia. Oncogene 24, 2410–2420 (2005). https://doi.org/10.1038/sj.onc.1208431
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208431
Keywords
This article is cited by
-
The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8+ T cell fates
Nature Immunology (2024)
-
Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis
Leukemia (2020)
-
MicroRNAs: pivotal regulators in acute myeloid leukemia
Annals of Hematology (2020)
-
SHP1 and SHP2 inhibition enhances the pro-differentiative effect of phorbol esters: an alternative approach against acute myeloid leukemia
Journal of Experimental & Clinical Cancer Research (2019)
-
Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia
Oncogene (2019)