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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 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 Citation Map 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 Myeloid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA CBFβ is critical for AML1-ETO and TEL-AML1 activity Liya Roudaia1,*, Matthew D. Cheney1,*, Ekaterina Manuylova1, Wei Chen1, Michelle Morrow2, Sangho Park3, Chung-Tsai Lee1,4, Prabhjot Kaur5, Owen Williams2, John H. Bushweller3,6, and Nancy A. Speck1,4 1 Department of Biochemistry, Dartmouth Medical School, Hanover, NH; 2 Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, United Kingdom; 3 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville; 4 Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia; 5 Department of Pathology, Dartmouth Medical School, Hanover, NH; and 6 Department of Chemistry, University of Virginia, Charlottesville 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 β (CBFβ) subunit. To determine whether CBFβ is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBFβ but not DNA binding. We show that CBFβ 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-PDGFβR in generating acute myeloid leukemia in mice. Similarly, CBFβ is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBFβ 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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