The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells.
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.
Aichberger
Karl J
KJ
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, AKH-Wien, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Mayerhofer
Matthias
M
Vales
Anja
A
Krauth
Maria-Theresa
MT
Gleixner
Karoline V
KV
Bilban
Martin
M
Esterbauer
Harald
H
Sonneck
Karoline
K
Florian
Stefan
S
Derdak
Sophia
S
Pickl
Winfried F
WF
Agis
Hermine
H
Falus
Andras
A
Sillaber
Christian
C
Valent
Peter
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D006632:Histamine / Q000096:biosynthesis*; D006633:Histamine Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011968:Receptors, Histamine / Q000032:analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006633:Histamine Antagonists; D015513:Oncogene Proteins; D011968:Receptors, Histamine; D006632:Histamine; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D006640:Histidine Decarboxylase