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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2002-12-3779. This Article Full Text (PDF) All Versions of this Article: 2002-12-3779v1 102/5/1857    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 Westervelt, P. Articles by Ley, T. J Search for Related Content PubMed PubMed Citation Articles by Westervelt, P. Articles by Ley, T. J Social Bookmarking                   What's this? Submitted December 13, 2002 Accepted May 4, 2003 A high penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RAR expression Peter Westervelt, Andrew A Lane, Jessica L Pollock, Kristie Oldfather, Matthew S Holt, Drazen B Zimonjic, Nicholas C Popescu, John F DiPersio, and Timothy J Ley* Division of Oncology, Departments of Medicine & Genetics, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA Molecular Cytogenetics Section, Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD, USA Hematology/Oncology Division, Massachusetts Medical School, Worcester, MA, USA * Corresponding author; email: tley{at}im.wustl.edu. Transgenic mice expressing PML-RAR in early myeloid cells under control of human cathepsin G regulatory sequences all develop a myeloproliferative syndrome, but only 15-20% develop acute promyelocytic leukemia (APL) after a latent period of 6-14 months. However, this transgene is expressed at very low levels in the bone marrow cells of transgenic mice. Since the transgene includes only 6 kB of regulatory sequences from the human cathepsin G locus, we hypothesized that sequences required for high-level expression of the transgene might be located elsewhere in the cathepsin G locus, and that a knock-in model might yield much higher expression levels, and higher penetrance of disease. We therefore targeted a human PML-RAR cDNA to the 5' untranslated region of the murine cathepsin G gene, using homologous recombination in embryonic stem cells. This model produced a high-penetrance APL phenotype, with more than 90% of knock-in mice developing APL between 6-16 months of age. The latent period and phenotype of APL (including a low frequency of an interstitial deletion of chromosome 2) was similar to that of the previous transgenic model. Remarkably, however, the expression level of PML-RAR in bone marrow cells or APL cells was <3% of that measured in the low-penetrance transgenic model. Although the explanation for this result is not yet clear, one hypothesis suggests that very low levels of PML-RAR expression in early myeloid cells may be optimal for the development of APL in mice. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Radaelli, F. Marchesi, V. Patton, and E. Scanziani Diagnostic Exercise: Sudden Death in a Mouse with Experimentally Induced Acute Myeloid Leukemia Vet. Pathol., November 1, 2009; 46(6): 1301 - 1305. [Abstract] [Full Text] [PDF] B. Nervi, P. Ramirez, M. P. Rettig, G. L. Uy, M. S. Holt, J. K. Ritchey, J. L. Prior, D. Piwnica-Worms, G. Bridger, T. J. Ley, et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100 Blood, June 11, 2009; 113(24): 6206 - 6214. 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