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, A. Falus, Christian Sillaber, Peter Valent

Research output: Contribution to journalArticle

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Abstract

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 up-regulated 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 (HRs), 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.

Original languageEnglish
Pages (from-to)3538-3547
Number of pages10
JournalBlood
Volume108
Issue number10
DOIs
Publication statusPublished - Nov 15 2006

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Histidine Decarboxylase
Histamine Receptors
Oncogene Proteins
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Histamine
Myeloid Cells
Basophils
fexofenadine
Isoenzymes
Loratadine
Terfenadine
Phosphatidylinositol 3-Kinases
Protein-Tyrosine Kinases
Histamine Antagonists
Cells
Drug Delivery Systems
Growth
Messenger RNA
Disease Progression

ASJC Scopus subject areas

  • Hematology

Cite this

Aichberger, K. J., Mayerhofer, M., Vales, A., Krauth, M. T., Gleixner, K. V., Bilban, M., ... Valent, P. (2006). The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells. Blood, 108(10), 3538-3547. https://doi.org/10.1182/blood-2005-12-028456

The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells. / Aichberger, Karl J.; Mayerhofer, Matthias; Vales, Anja; Krauth, Maria Theresa; Gleixner, Karoline V.; Bilban, Martin; Esterbauer, Harald; Sonneck, Karoline; Florian, Stefan; Derdak, Sophia; Pickl, Winfried F.; Agis, Hermine; Falus, A.; Sillaber, Christian; Valent, Peter.

In: Blood, Vol. 108, No. 10, 15.11.2006, p. 3538-3547.

Research output: Contribution to journalArticle

Aichberger, KJ, Mayerhofer, M, Vales, A, Krauth, MT, Gleixner, KV, Bilban, M, Esterbauer, H, Sonneck, K, Florian, S, Derdak, S, Pickl, WF, Agis, H, Falus, A, Sillaber, C & Valent, P 2006, 'The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells', Blood, vol. 108, no. 10, pp. 3538-3547. https://doi.org/10.1182/blood-2005-12-028456
Aichberger, Karl J. ; Mayerhofer, Matthias ; Vales, Anja ; Krauth, Maria Theresa ; Gleixner, Karoline V. ; Bilban, Martin ; Esterbauer, Harald ; Sonneck, Karoline ; Florian, Stefan ; Derdak, Sophia ; Pickl, Winfried F. ; Agis, Hermine ; Falus, A. ; Sillaber, Christian ; Valent, Peter. / The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells. In: Blood. 2006 ; Vol. 108, No. 10. pp. 3538-3547.
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abstract = "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 up-regulated 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 (HRs), 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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AU - Krauth, Maria Theresa

AU - Gleixner, Karoline V.

AU - Bilban, Martin

AU - Esterbauer, Harald

AU - Sonneck, Karoline

AU - Florian, Stefan

AU - Derdak, Sophia

AU - Pickl, Winfried F.

AU - Agis, Hermine

AU - Falus, A.

AU - Sillaber, Christian

AU - Valent, Peter

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N2 - 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 up-regulated 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 (HRs), 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.

AB - 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 up-regulated 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 (HRs), 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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