Original Article

Leukemia accepted article preview 31 July 2017; doi: 10.1038/leu.2017.245

This is an unedited manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Nilotinib-induced vasculopathy: Identification of vascular endothelial cells as a primary target site

E Hadzijusufovic1,2,3,13, K Albrecht-Schgoer4,5,13, K Huber6, G Hoermann7, F Grebien6,8, G Eisenwort1, W Schgoer4, S Herndlhofer2, C Kaun9, M Theurl4, W R Sperr1,2, U Rix6, I Sadovnik2, B Jilma10, G H Schernthaner11, J Wojta8, D Wolf12, G Superti-Furga6, R Kirchmair4 and P Valent1,2

  1. 1Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria
  2. 2Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
  3. 3Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Austria
  4. 4Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Austria
  5. 5Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Medical University of Innsbruck, Austria
  6. 6Research Center for Molecular Medicine (CeMM), Vienna, Austria
  7. 7Department of Laboratory Medicine, Medical University of Vienna, Austria
  8. 8Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  9. 9Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria
  10. 10Department of Clinical Pharmacology, Medical University of Vienna, Austria
  11. 11Department of Internal Medicine II, Division of Angiology, Medical University of Vienna, Austria
  12. 12Medical Clinic 3, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Germany

Correspondence: R Kirchmair, Department of Internal Medicine III, Medical University of Innsbruck, Cardiology and Angiology, Anichstrasse 35, Innsbruck 6020, Austria. E-mail: rudolf.kirchmair@i-med.ac.at; Professor P Valent, Department of Internal Medicine I, Division of Hematology & Hemostaseology and Hemostaseology and Ludwig Boltzmann Cl, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria. E-mail: peter.valent@meduniwien.ac.at

13These authors contributed equally to this work.

Received 22 April 2017; Revised 13 July 2017; Accepted 17 July 2017
Accepted article preview online 31 July 2017

Top

Abstract

The BCR/ABL1 inhibitor Nilotinib is increasingly used to treat patients with chronic myeloid leukemia (CML). Although otherwise well-tolerated, Nilotinib has been associated with the occurrence of progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine in vitro and in vivo 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. Nilotinib and siRNA against ABL-2 also suppressed KDR expression. In addition, Nilotinib augmented atherosclerosis in ApoE−/− mice and blocked reperfusion and angiogenesis in a hind-limb-ischemia model of arterial occlusion, whereas Imatinib showed no comparable effects. Clinically overt AOD-events were found to accumulate over time in Nilotinib-treated patients. After a median observation-time of 2.0 years, the AOD-frequency was higher in these patients (29.4%) compared to risk factor- and age-matched controls (<5%). 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.