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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3538-3547. Prepublished online as a Blood First Edition Paper on July 18, 2006; DOI 10.1182/blood-2005-12-028456. This Article Full Text (PDF) All Versions of this Article: blood-2005-12-028456v1 108/10/3538    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 Aichberger, K. J Articles by Valent, P. Search for Related Content PubMed PubMed Citation Articles by Aichberger, K. J Articles by Valent, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 20, 2005 Accepted July 6, 2006 The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells Karl J Aichberger, Matthias Mayerhofer, Anja Vales, Maria-Theresa Krauth, Karoline V Gleixner, Martin Bilban, Harald Esterbauer, Karoline Sonneck, Stefan Florian, Sophia Derdak, Winfried F Pickl, Hermine Agis, Andras Falus, Christian Sillaber, and Peter Valent* Department of Internal Medicine I, Division of Hematology and Hemostaseology, Med. Univ. of Vienna Cinical Institute of Med. and Chem. Laboratory Diagnostics, Med. Univ. of Vienna Institute of Immunology, Med. Univ. of Vienna Department of Genetics, Semmelweis University of Medicine, Budapest, Hungary * Corresponding author; email: peter.valent{at}meduniwien.ac.at. Basophil numbers are typically elevated in chronic myeloid leukemia (CML) and increase during disease- progression. Histamine is an essential mediator and marker of basophils and is highly upregulated in CML. We examined the biochemical basis of histamine-synthesis in CML cells. The CML-specific oncoprotein BCR/ABL was found to promote expression of histidine decarboxylase (HDC) and synthesis of histamine in Ba/F3 cells. Moreover, the BCR/ABL tyrosine kinase inhibitors imatinib/STI571 and nilotinib/AMN107 decreased histamine- levels and HDC mRNA-expression in BCR/ABL-transformed Ba/F3 cells, in the CML-derived basophil cell line KU812, and in primary CML cells. Synthesis of histamine was found to be restricted to the basophil-compartment of the CML-clone, and to depend on signaling through the PI3-kinase-pathway. CML cells also expressed histamine receptors (HR) including HR-1, HR-2, HR-4, and histamine- binding CYP450-isoenzymes which also serve as targets of HR-antagonists. The HR-1-antagonists loratadine and terfenadine, which bind to CYP450, were found to counteract proliferation of CML cells, whereas no growth- inhibition was observed with the HR-1-antagonist fexofenadine which is not targeted or metabolized by CYP450. Moreover, DPPE, an inhibitor of histamine- binding CYP450-isoenzymes, produced growth-inhibition in CML cells. Together, these data show that BCR/ABL promotes histamine-production in CML cells, and that certain HR-targeting drugs exert antileukemic effects on CML cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Biosse-Duplan, B. Baroukh, M. Dy, M.-C. de Vernejoul, and J.-L. Saffar Histamine Promotes Osteoclastogenesis through the Differential Expression of Histamine Receptors on Osteoclasts and Osteoblasts Am. J. Pathol., April 1, 2009; 174(4): 1426 - 1434. [Abstract] [Full Text] [PDF]

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