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J. Biol. Chem., Vol. 280, Issue 48, 40097-40103, December 2, 2005

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The inv(16) Cooperates with ARF Haploinsufficiency to Induce Acute Myeloid Leukemia^*

Isabel Moreno-Miralles1, Ling Pan1, Jennifer Keates-Baleeiro, Kristie Durst-Goodwin, Chunying Yang¶, Hyung-Gyoon Kim||, Mary Ann Thompson**, Christopher A. Klug||, John L. Cleveland¶, and Scott W. Hiebert2

From the Departments of Biochemistry and Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232 ^¶Department of Biochemistry, St. Jude Children's Research Hospital, and Department of Molecular Sciences, University of Tennessee, Memphis, Tennessee, 38105 ^||Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294 ^**Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

The inv(16) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML) and creates a chimeric fusion protein consisting of most of the runt-related X1 co-factor, core binding factor fused to the smooth muscle myosin heavy chain MYH11. Expression of the ARF tumor suppressor is regulated by runt-related X1, suggesting that the inv(16) fusion protein (IFP) may repress ARF expression. We established a murine bone marrow transplant model of the inv(16) in which wild type, Arf^+/-, and Arf^-/- bone marrow were engineered to express the IFP. IFP expression was sufficient to induce a myelomonocytic AML even when expressed in wild type bone marrow, yet removal of only a single allele of Arf greatly accelerated the disease, indicating that Arf is haploinsufficient for the induction of AML in the presence of the inv(16).

Received for publication, June 23, 2005 , and in revised form, September 26, 2005.

^* This work was supported by Vanderbilt-Ingram Cancer Center Grant CA68485 and National Institutes of Health Grants RO1-CA87549, RO1-CA64140, RO1-CA77274 (to S. W. H.) and RO1-CA76379 (to J. L. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt University School of Medicine, PRB 512, 23rd and Pierce, Nashville, Tennessee 37232. Tel.: 615-936-3582; Fax: 615-936-1790; E-mail: scott.hiebert{at}vanderbilt.edu.

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