Basophil numbers are typically elevated in patients with chronic myeloid leukemia (CML) and characteristically increase during disease progression. As a consequence, blood histamine levels are highly upregulated in CML. We examined the biochemical basis of production of histamine in CML cells and analyzed the effects of the CML-related oncoprotein BCR/ABL on the generation of this mediator. Expression of histamine and of histidine decarboxylase (HDC), the major enzyme involved in histamine synthesis, were examined in primary CML cells obtained from patients with chronic phase (CP) CML or accelerated phase (AP) CML with basophilia, in the CML-derived cell lines K562 and KU812, and in Ba/F3 cells inducibly expressing BCR/ABL on exposure to doxycycline (TonB.210-X cells). In all patients with AP-CML and basophilia, high levels of HDC mRNA and of histamine were detected, whereas in CP-CML cells only expressed low amounts of HDC and of histamine. HDC mRNA and histamine were detectable in the basophil-committed CML cell line KU812, but not in K562 cells. Exposure of primary CML cells or KU812 cells to the BCR/ABL tyrosine kinase inhibitors imatinib (1 μM; Novartis Pharma AG) or AMN107 (100 nM; Novartis Pharma AG) decreased the levels of histamine and expression of HDC in BCR/ABL-transformed cells. Moreover, BCR/ABL was found to promote the expression of HDC mRNA and to increase the levels of histamine in TonB.210-X cells. The BCR/ABL-induced synthesis of histamine in these cells was blocked by the PI3-kinase inhibitor LY294002, whereas neither the MEK inhibitor PD98059, nor the mTOR inhibitor rapamycin affected histamine levels. In conclusion, our data show that the CML-specific oncoprotein BCR/ABL induces expression of HDC and synthesis of histamine in leukemic cells through a pathway involving the PI3-kinase.