This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Müller-Tidow, C.
Right arrow Articles by Serve, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Müller-Tidow, C.
Right arrow Articles by Serve, H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2004, p. 2890-2904, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2890-2904.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells

Carsten Müller-Tidow,1,{dagger}* Björn Steffen,1,{dagger} Thomas Cauvet,1 Lara Tickenbrock,1 Ping Ji,1 Sven Diederichs,1 Bülent Sargin,1 Gabriele Köhler,2 Matthias Stelljes,1 Elena Puccetti,3 Martin Ruthardt,3 Sven deVos,4 Scott W. Hiebert,5 H. Phillip Koeffler,4 Wolfgang E. Berdel,1 and Hubert Serve1

Department of Medicine, Hematology and Oncology,1 Gerhard Domagk Institute of Pathology, University of Münster, Münster,2 Department of Internal Medicine III, Goethe University, Frankfurt, Germany,3 Division of Hematology and Oncology, Cedars-Sinai Medical Center/University of California—Los Angeles School of Medicine, Los Angeles, California,4 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee5

Received 1 August 2003/ Returned for modification 8 October 2003/ Accepted 5 January 2004

The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RAR{alpha}), and PLZF-RAR{alpha} encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RAR{alpha}, or PLZF-RAR{alpha}. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin ({gamma}-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. ß-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.

* Corresponding author. Mailing address: Dept. of Medicine, Hematology/Oncology, University of Münster, Domagkstr. 3, 48129 Münster, Germany. Phone: 49-251-835-2995. Fax: 49-251-835-2673. E-mail: muellerc{at}uni-muenster.de.

{dagger} C.M.-T. and B.S. contributed equally.

Molecular and Cellular Biology, April 2004, p. 2890-2904, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2890-2904.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yan, M., Ahn, E.-Y., Hiebert, S. W., Zhang, D.-E. (2009). RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis. Blood 113: 883-886 [Abstract] [Full Text]  
  • Berg, T., Fliegauf, M., Burger, J., Staege, M. S., Liu, S., Martinez, N., Heidenreich, O., Burdach, S., Haferlach, T., Werner, M. H., Lubbert, M. (2008). Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO. haematol 93: 1728-1733 [Abstract] [Full Text]  
  • Dolniak, B., Katsoulidis, E., Carayol, N., Altman, J. K., Redig, A. J., Tallman, M. S., Ueda, T., Watanabe-Fukunaga, R., Fukunaga, R., Platanias, L. C. (2008). Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2. J. Biol. Chem. 283: 12034-12042 [Abstract] [Full Text]  
  • Dayyani, F., Wang, J., Yeh, J.-R. J., Ahn, E.-Y., Tobey, E., Zhang, D.-E., Bernstein, I. D., Peterson, R. T., Sweetser, D. A. (2008). Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival. Blood 111: 4338-4347 [Abstract] [Full Text]  
  • Hoemme, C., Peerzada, A., Behre, G., Wang, Y., McClelland, M., Nieselt, K., Zschunke, M., Disselhoff, C., Agrawal, S., Isken, F., Tidow, N., Berdel, W. E., Serve, H., Muller-Tidow, C. (2008). Chromatin modifications induced by PML-RAR{alpha} repress critical targets in leukemogenesis as analyzed by ChIP-Chip. Blood 111: 2887-2895 [Abstract] [Full Text]  
  • Moore, A. C., Amann, J. M., Williams, C. S., Tahinci, E., Farmer, T. E., Martinez, J. A., Yang, G., Luce, K. S., Lee, E., Hiebert, S. W. (2008). Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription. Mol. Cell. Biol. 28: 977-987 [Abstract] [Full Text]  
  • Jeannet, G., Scheller, M., Scarpellino, L., Duboux, S., Gardiol, N., Back, J., Kuttler, F., Malanchi, I., Birchmeier, W., Leutz, A., Huelsken, J., Held, W. (2008). Long-term, multilineage hematopoiesis occurs in the combined absence of -catenin and {gamma}-catenin. Blood 111: 142-149 [Abstract] [Full Text]  
  • Peterson, L. F., Yan, M., Zhang, D.-E. (2007). The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO. Blood 109: 4392-4398 [Abstract] [Full Text]  
  • Agrawal, S., Hofmann, W.-K., Tidow, N., Ehrich, M., Boom, D. v. d., Koschmieder, S., Berdel, W. E., Serve, H., Muller-Tidow, C. (2007). The C/EBP{delta} tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood 109: 3895-3905 [Abstract] [Full Text]  
  • Roman-Gomez, J., Cordeu, L., Agirre, X., Jimenez-Velasco, A., San Jose-Eneriz, E., Garate, L., Calasanz, M. J., Heiniger, A., Torres, A., Prosper, F. (2007). Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia. Blood 109: 3462-3469 [Abstract] [Full Text]  
  • Wichmann, C., Chen, L., Heinrich, M., Baus, D., Pfitzner, E., Zornig, M., Ottmann, O. G., Grez, M. (2007). Targeting the Oligomerization Domain of ETO Interferes with RUNX1/ETO Oncogenic Activity in t(8;21)-Positive Leukemic Cells. Cancer Res. 67: 2280-2289 [Abstract] [Full Text]  
  • Baba, Y., Yokota, T., Spits, H., Garrett, K. P., Hayashi, S.-I., Kincade, P. W. (2006). Constitutively Active beta-Catenin Promotes Expansion of Multipotent Hematopoietic Progenitors in Culture. J. Immunol. 177: 2294-2303 [Abstract] [Full Text]  
  • Choi, Y., Elagib, K. E., Delehanty, L. L., Goldfarb, A. N. (2006). Erythroid Inhibition by the Leukemic Fusion AML1-ETO Is Associated with Impaired Acetylation of the Major Erythroid Transcription Factor GATA-1.. Cancer Res. 66: 2990-2996 [Abstract] [Full Text]  
  • Liu, T.-H., Raval, A., Chen, S.-S., Matkovic, J. J., Byrd, J. C., Plass, C. (2006). CpG Island Methylation and Expression of the Secreted Frizzled-Related Protein Gene Family in Chronic Lymphocytic Leukemia. Cancer Res. 66: 653-658 [Abstract] [Full Text]  
  • Luo, H., Li, Q., O'Neal, J., Kreisel, F., Le Beau, M. M., Tomasson, M. H. (2005). c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. Blood 106: 2452-2461 [Abstract] [Full Text]  
  • Bullinger, L., Valk, P. J.M. (2005). Gene Expression Profiling in Acute Myeloid Leukemia. JCO 23: 6296-6305 [Abstract] [Full Text]  
  • Tickenbrock, L., Schwable, J., Wiedehage, M., Steffen, B., Sargin, B., Choudhary, C., Brandts, C., Berdel, W. E., Muller-Tidow, C., Serve, H. (2005). Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood 105: 3699-3706 [Abstract] [Full Text]  
  • Mulloy, J. C., Jankovic, V., Wunderlich, M., Delwel, R., Cammenga, J., Krejci, O., Zhao, H., Valk, P. J. M., Lowenberg, B., Nimer, S. D. (2005). AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. Proc. Natl. Acad. Sci. USA 102: 4016-4021 [Abstract] [Full Text]  
  • Schwable, J., Choudhary, C., Thiede, C., Tickenbrock, L., Sargin, B., Steur, C., Rehage, M., Rudat, A., Brandts, C., Berdel, W. E., Muller-Tidow, C., Serve, H. (2005). RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation. Blood 105: 2107-2114 [Abstract] [Full Text]  
  • Licht, J. D., Sternberg, D. W. (2005). The Molecular Pathology of Acute Myeloid Leukemia. ASH Education Book 2005: 137-142 [Abstract] [Full Text]  
  • Muller-Tidow, C., Ji, P., Diederichs, S., Potratz, J., Baumer, N., Kohler, G., Cauvet, T., Choudary, C., van der Meer, T., Chan, W.-Y. I., Nieduszynski, C., Colledge, W. H., Carrington, M., Koeffler, H. P., Restle, A., Wiesmuller, L., Sobczak-Thepot, J., Berdel, W. E., Serve, H. (2004). The Cyclin A1-CDK2 Complex Regulates DNA Double-Strand Break Repair. Mol. Cell. Biol. 24: 8917-8928 [Abstract] [Full Text]  
  • Diederichs, S., Bulk, E., Steffen, B., Ji, P., Tickenbrock, L., Lang, K., Zanker, K. S., Metzger, R., Schneider, P. M., Gerke, V., Thomas, M., Berdel, W. E., Serve, H., Muller-Tidow, C. (2004). S100 Family Members and Trypsinogens Are Predictors of Distant Metastasis and Survival in Early-Stage Non-Small Cell Lung Cancer. Cancer Res. 64: 5564-5569 [Abstract] [Full Text]  
  • Zheng, X., Beissert, T., Kukoc-Zivojnov, N., Puccetti, E., Altschmied, J., Strolz, C., Boehrer, S., Gul, H., Schneider, O., Ottmann, O. G., Hoelzer, D., Henschler, R., Ruthardt, M. (2004). {gamma}-Catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells. Blood 103: 3535-3543 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»