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Nilotinib contributes to arterial occlusive disease in CML-patients

Chronic myeloid leukemia (CML) is increasingly treated with the BCR/ABL1 inhibitor Nilotinib. Although otherwise well-tolerated, Nilotinib has been associated with progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine effects of Nilotinib and Imatinib on endothelial cells to explain AOD-development. In contrast to Imatinib, Nilotinib was found to upregulate pro-atherogenic adhesion-proteins (ICAM-1, E-selectin, VCAM-1) on human endothelial cells. Nilotinib also suppressed endothelial cell proliferation, migration and tube-formation, and bound to a distinct set of target-kinases, relevant to angiogenesis and atherosclerosis, including angiopoietin receptor-1 TEK, ABL-2, JAK1, and MAP-kinases, whereas Imatinib showed no comparable effects. Clinically overt AOD-events were found to accumulate over time in Nilotinib-treated patients. Together, Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells, which may contribute to development of AOD in patients with CML. These findings were now published with a contribution of researchers from the LBI-CR in Leukemia of the Nature Publishing Group.