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Blood, 26 March 2009, Vol. 113, No. 13, pp. 3070-3079. Prepublished online as a Blood First Edition Paper on January 29, 2009; DOI 10.1182/blood-2008-03-147207. This Article Full Text (PDF) All Versions of this Article: blood-2008-03-147207v1 113/13/3070    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Roudaia, L. Articles by Speck, N. A Search for Related Content PubMed PubMed Citation Articles by Roudaia, L. Articles by Speck, N. A Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 25, 2008 Accepted January 11, 2009 CBF is critical for AML1-ETO and TEL-AML1 activity Liya Roudaia, Matthew D. Cheney, Ekaterina Manuylova, Wei Chen, Michelle Morrow, Sangho Park, Chung-Tsai Lee, Prabhjot Kaur, Owen Williams, John H. Bushweller, and Nancy A Speck* Department of Biochemistry, Dartmouth Medical School, Hanover, NH, United States Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, United Kingdom Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, United States Department of Pathology, Dartmouth Medical School, Hanover, NH, United States Department of Chemistry, University of Virginia, Charlottesville, VA, United States * Corresponding author; email: nancyas{at}exchange.upenn.edu. AML1-ETO and TEL-AML1 are chimeric proteins resulting from the t(8;21)(q22;q22) in acute myeloid leukemia, and the t(12;21)(p13;q22) in pre-B cell leukemia, respectively. The Runt domain of AML1 in both proteins mediates DNA binding and heterodimerization with the core binding factor beta (CBF) subunit. To determine whether CBF is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBF but not DNA binding. We show that CBF contributes to AML1-ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and is indispensable for its cooperativity with the activated receptor tyrosine kinase TEL-PDGFR in generating acute myeloid leukemia in mice. Similarly, CBF is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBF interaction as a therapeutic target in core binding factor leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The role of CBFβ in AML1-ETO's activity Sangho Park, Nancy A. Speck, and John H. Bushweller Blood 2009 114: 2849-2850. [Full Text] [PDF] This article has been cited by other articles: J. L. Barton, D. H. J. Bunka, S. E. Knowling, P. Lefevre, A. J. Warren, C. Bonifer, and P. G. Stockley Characterization of RNA aptamers that disrupt the RUNX1-CBF{beta}/DNA complex Nucleic Acids Res., November 1, 2009; 37(20): 6818 - 6830. [Abstract] [Full Text] [PDF] S. Park, N. A. Speck, and J. H. Bushweller The role of CBF{beta} in AML1-ETO's activity Blood, September 24, 2009; 114(13): 2849 - 2850. [Full Text] [PDF] S. Park, W. Chen, T. Cierpicki, M. Tonelli, X. Cai, N. A. Speck, and J. H. Bushweller Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity Blood, April 9, 2009; 113(15): 3558 - 3567. [Abstract] [Full Text] [PDF]

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