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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3373-3382. Prepublished online as a Blood First Edition Paper on July 28, 2008; DOI 10.1182/blood-2008-03-147587. This Article Full Text (PDF) All Versions of this Article: blood-2008-03-147587v1 112/8/3373    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 Kindler, T. Articles by Gilliland, D G. Search for Related Content PubMed PubMed Citation Articles by Kindler, T. Articles by Gilliland, D G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 26, 2008 Accepted July 7, 2008 K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to -secretase inhibitors Thomas Kindler*, Melanie G Cornejo, Claudia Scholl, Jianing Liu, Dena S Leeman, J Erika Haydu, Stefan Frohling, Benjamin H Lee, and D Gary Gilliland Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States Department of Medical Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, MA, United States * Corresponding author; email: thomas.kindler{at}ukmainz.de. To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-RasG12D murine knock-in model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were comprised of a CD4/CD8 double positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double negative (DN) 1 stage. With progression of disease, 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to -secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by downregulation of Notch1 target genes and intracellular cleaved Notch (ICN). We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone, or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Xu, X. Liu, J. Chen, A. Zacharek, X. Cui, S. Savant-Bhonsale, Z. Liu, and M. Chopp Simvastatin enhances bone marrow stromal cell differentiation into endothelial cells via notch signaling pathway Am J Physiol Cell Physiol, March 1, 2009; 296(3): C535 - C543. [Abstract] [Full Text] [PDF]

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