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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1357-1365. Prepublished online as a Blood First Edition Paper on May 23, 2008; DOI 10.1182/blood-2007-06-094060. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-06-094060v1 112/4/1357    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 Wahlstrom, A. M. Articles by Bergo, M. O. Search for Related Content PubMed PubMed Citation Articles by Wahlstrom, A. M. Articles by Bergo, M. O. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inactivating Icmt ameliorates K-RAS–induced myeloproliferative disease Annika M. Wahlstrom1,*, Briony A. Cutts1,*, Meng Liu1,2, Annika Lindskog1, Christin Karlsson1, Anna-Karin M. Sjogren1, Karin M. E. Andersson1, Stephen G. Young3, and Martin O. Bergo1 1 Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; 2 Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, China; and 3 Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles Hyperactive signaling through the RAS proteins is involved in the pathogenesis of many forms of cancer. The RAS proteins and many other intracellular signaling proteins are either farnesylated or geranylgeranylated at a carboxyl-terminal cysteine. That isoprenylcysteine is then carboxyl methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). We previously showed that inactivation of Icmt mislocalizes the RAS proteins away from the plasma membrane and blocks RAS transformation of mouse fibroblasts, suggesting that ICMT could be a therapeutic target. However, nothing is known about the impact of inhibiting ICMT on the development of malignancies in vivo. In the current study, we tested the hypothesis that inactivation of Icmt would inhibit the development or progression of a K-RAS–induced myeloproliferative disease in mice. We found that inactivating Icmt reduced splenomegaly, the number of immature myeloid cells in peripheral blood, and tissue infiltration by myeloid cells. Moreover, in the absence of Icmt, the ability of K-RAS–expressing hematopoietic cells to form colonies in methylcellulose without exogenous growth factors was reduced dramatically. Finally, inactivating Icmt reduced lung tumor development and myeloproliferation phenotypes in a mouse model of K-RAS–induced cancer. We conclude that inactivation of Icmt ameliorates phenotypes of K-RAS–induced malignancies in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. A. Cutts, A.-K. M. Sjogren, K. M. E. Andersson, A. M. Wahlstrom, C. Karlsson, B. Swolin, and M. O. Bergo Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice Blood, October 22, 2009; 114(17): 3629 - 3632. [Abstract] [Full Text] [PDF] L. P. Wright, H. Court, A. Mor, I. M. Ahearn, P. J. Casey, and M. R. Philips Topology of Mammalian Isoprenylcysteine Carboxyl Methyltransferase Determined in Live Cells with a Fluorescent Probe Mol. Cell. Biol., April 1, 2009; 29(7): 1826 - 1833. [Abstract] [Full Text] [PDF]

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