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 Yang, G.
Right arrow Articles by Hiebert, S. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, G.
Right arrow Articles by Hiebert, S. W.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2005, p. 5869-5879, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.5869-5879.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transcriptional Repression of the Neurofibromatosis-1 Tumor Suppressor by the t(8;21) Fusion Protein

Genyan Yang,1 Waleed Khalaf,2 Louis van de Locht,3 Joop H. Jansen,3 Meihua Gao,4 Mary Ann Thompson,5 Bert A. van der Reijden,3 David H. Gutmann,6 Ruud Delwel,7 D. Wade Clapp,2 and Scott W. Hiebert1,8*

Department of Biochemistry,1 Department of Pathology,5 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,8 Departments of Microbiology, Immunology and Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana,2 Department of Hematology, University Medical Center St. Radboud, Nijmegen,3 Department of Hematology, Erasmus University, Rotterdam, The Netherlands,7 Department of Mathematics, Middle Tennessee State University, Murfreesboro, Tennessee 37132,4 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 631106

Received 9 November 2004/ Returned for modification 19 January 2005/ Accepted 14 April 2005

Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are not common in acute myeloid leukemia (AML). Given that the RUNX1 transcription factor is the most common target for chromosomal translocations in acute leukemia, we asked if NF1 might be regulated by RUNX1. In reporter assays, RUNX1 activated the NF1 promoter and cooperated with C/EBP{alpha} and ETS2 to activate the NF1 promoter over 80-fold. Moreover, the t(8;21) fusion protein RUNX1-MTG8 (R/M), which represses RUNX1-regulated genes, actively repressed the NF1 promoter. R/M associated with the NF1 promoter in vivo and repressed endogenous NF1 gene expression. In addition, similar to loss of NF1, R/M expression enhanced the sensitivity of primary myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor. Our results indicate that the NF1 tumor suppressor gene is a direct transcriptional target of RUNX1 and the t(8;21) fusion protein, suggesting that suppression of NF1 expression contributes to the molecular pathogenesis of AML.

* Corresponding author. Mailing address: Department of Biochemistry, Vanderbilt University School of Medicine, PRB 512, 23rd and Pierce, Nashville, TN 37232. Phone: (615) 936-3582. Fax: (615) 936-1790. E-mail: scott.hiebert{at}vanderbilt.edu.

Molecular and Cellular Biology, July 2005, p. 5869-5879, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.5869-5879.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Koenigsmann, J., Rudolph, C., Sander, S., Kershaw, O., Gruber, A. D., Bullinger, L., Schlegelberger, B., Carstanjen, D. (2009). Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias. Blood 113: 4690-4701 [Abstract] [Full Text]  
  • Cheng, C. K., Li, L., Cheng, S. H., Lau, K. M., Chan, N. P. H., Wong, R. S. M., Shing, M. M. K., Li, C. K., Ng, M. H. L. (2008). Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia. Blood 112: 3391-3402 [Abstract] [Full Text]  
  • Moreno-Miralles, I., Pan, L., Keates-Baleeiro, J., Durst-Goodwin, K., Yang, C., Kim, H.-G., Thompson, M. A., Klug, C. A., Cleveland, J. L., Hiebert, S. W. (2005). The inv(16) Cooperates with ARF Haploinsufficiency to Induce Acute Myeloid Leukemia. J. Biol. Chem. 280: 40097-40103 [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»