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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3200-3207. Prepublished online as a Blood First Edition Paper on December 24, 2003; DOI 10.1182/blood-2003-07-2188. This Article Full Text (PDF) All Versions of this Article: 2003-07-2188v1 103/8/3200    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 Huang, G. Articles by Ito, Y. Search for Related Content PubMed PubMed Citation Articles by Huang, G. Articles by Ito, Y. Social Bookmarking                   What's this? Submitted July 2, 2003 Accepted December 6, 2003 Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera Gang Huang, Katsuya Shigesada, Hee-Jun Wee, P Paul Liu, Motomi Osato, and Yoshiaki Ito* Laboratory of Molecular Oncology, Institute of Molecular and Cell Biology, Singapore, Singapore; Oncology Research Institute, National University of Singapore, Singapore, Singapore Institute for Virus Research, Kyoto University, Kyoto, Japan National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA * Corresponding author; email: itoy{at}imcb.a-star.edu.sg. The Runt domain transcription factor, PEBP2/CBF, is a heterodimer composed of two subunits. The DNA binding subunit, or RUNX protein, interacts with a partner PEBP2/CBF through the evolutionarily conserved Runt domain. Each of the genes encoding RUNX1 and PEBP2/CBF is frequently involved in acute myeloid leukemia. The chimeric protein, CBF(PEBP2)/SMMHC, is generated as a result of inversion of chromosome 16 in such a way to retain the heterodimerization domain of PEBP2 at the amino-terminal side fused to the C-terminal coiled-coil region of smooth muscle myosin heavy chain (SMMHC). Here we show that, in the chimeric protein, the second heterodimerization domain is created by the fusion junction, enabling the chimeric protein to interact with RUNX1 at far greater affinity than PEBP2 and inactivate the RUNX1/AML1 function. To explain why and how heterozygous CBFB/MYH11 can inactivate homozygous RUNX1 near to completion, we propose a new model for this chimeric protein that consists of a Y-shaped dimer with unpaired N-terminal halves followed by a coiled-coil for the C-terminal region. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H.-J. Wee, D. C.-C. Voon, S.-C. Bae, and Y. Ito PEBP2-{beta}/CBF-{beta}-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis Blood, November 1, 2008; 112(9): 3777 - 3787. [Abstract] [Full Text] [PDF] T. Yokomizo, K. Hasegawa, H. Ishitobi, M. Osato, M. Ema, Y. Ito, M. Yamamoto, and S. Takahashi Runx1 is involved in primitive erythropoiesis in the mouse Blood, April 15, 2008; 111(8): 4075 - 4080. [Abstract] [Full Text] [PDF] H.-G. Kim, K. Kojima, C. S. Swindle, C. V. Cotta, Y. Huo, V. Reddy, and C. A. Klug FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia Blood, February 1, 2008; 111(3): 1567 - 1574. [Abstract] [Full Text] [PDF] J. Markus, M. T. Garin, J. Bies, N. Galili, A. Raza, M. J. Thirman, M. M. Le Beau, J. D. Rowley, P. P. Liu, and L. Wolff Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBF{beta}-SMMHC in Acute Myelogenous Leukemia with inv(16) Cancer Res., February 1, 2007; 67(3): 992 - 1000. [Abstract] [Full Text] [PDF]

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