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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1355-1361. Prepublished online as a Blood First Edition Paper on April 28, 2005; DOI 10.1182/blood-2004-09-3655. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3655v1 106/4/1355    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 Zhang, B. Articles by Heisterkamp, N. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Heisterkamp, N. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a Bin Zhang, John Groffen, and Nora Heisterkamp From the Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, CA; and the Keck School of Medicine, University of Southern California, Los Angeles, CA. Resistance to cytotoxic drugs frequently emerges during treatment of leukemia with conventional chemotherapy. New classes of anticancer drugs, such as the farnesyltransferase inhibitors (FTIs), show therapeutic promise, but whether cells will easily develop resistance against them is not known. Here, we grew breakpoint cluster region/Abelson murine leukemia (Bcr/Abl) P190 lymphoblasts on stroma and made them resistant to the FTI SCH66336lonafarnib to model emerging drug resistance in a patient. These cells exhibited greatly increased (> 100-fold) expression levels of a novel ATP (adenosine triphosphate)-binding cassette (ABC) transporter-homologous gene, ATP11A. We showed that overexpression of this gene provided protection against the effects of SCH66336 whereas knockdown of endogenous ATP11a using small interfering RNA (siRNA) made cells more sensitive to this drug. The lymphoblasts that were resistant to this FTI were also more resistant to FTI-276 and to GGTI-298, 2 other structurally similar inhibitors. Surprisingly, the cells were also able to survive higher concentrations of imatinib mesylate, the Bcr/Abl tyrosine kinase inhibitor. However, the cells remained sensitive to vincristine. Our results show that elevated levels of ATP11a can protect malignant lymphoblastic leukemia cells against several novel small molecule signal transduction inhibitors. A determination of the expression levels of this gene may have prognostic value when treatment with such classes of drugs is contemplated. (Blood. 2005;106: 1355-1361) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Raz, V. Nardi, M. Azam, J. Cortes, and G. Q. Daley Farnesyl transferase inhibitor resistance probed by target mutagenesis Blood, September 15, 2007; 110(6): 2102 - 2109. [Abstract] [Full Text] [PDF]

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