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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.
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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.
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