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Chronic myelogenous leukemia

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

Leukemia volume 31, pages 2388–2397 (2017)Cite this article

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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 hindlimb-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.

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Acknowledgements

We thank Sabine Cerny-Reiterer, Michael Kundi, Verena Suppan, Gabriele Stefanzl, Daniela Berger, Michael Gurbisz, Irina Mirkina, Sarah Vittori, Daniela Lener, Ursula Stanzl and Christoph Seger for excellent technical assistance. This study was supported in part by research funding from Novartis Oncology to PV and the Austrian Science Fund (FWF): F 4701-B20, F 4704-B20, F 5404-B20, and F 5412-B20.

Author contributions

EH, KAS, GE, IS, CK and JW performed experiments on cultured endothelial cells. KH, FG, UR and GSF performed proteomics and MS studies. WS, MT and RK performed experiments in mice. GH performed molecular studies. BJ performed studies on platelet adhesion and aggregation. SH, GHS, WRS and PV provided patients and analyzed the clinical and laboratory results. EH, DW, RK and PV drafted parts of the manuscript. EH and PV established the study concept and wrote the final paper-draft.

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Author notes

  1. E Hadzijusufovic and K Albrecht-Schgoer: These authors contributed equally to this work.

Authors and Affiliations

  1. Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria

    E Hadzijusufovic, G Eisenwort, W R Sperr & P Valent

  2. Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

    E Hadzijusufovic, S Herndlhofer, W R Sperr, I Sadovnik & P Valent

  3. Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria

    E Hadzijusufovic

  4. Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria

    K Albrecht-Schgoer, W Schgoer, M Theurl & R Kirchmair

  5. Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria

    K Albrecht-Schgoer

  6. Research Center for Molecular Medicine (CeMM), Vienna, Austria

    K Huber, F Grebien, U Rix & G Superti-Furga

  7. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    G Hoermann

  8. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    F Grebien

  9. Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria

    C Kaun & J Wojta

  10. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

    B Jilma

  11. Department of Internal Medicine II, Division of Angiology, Medical University of Vienna, Vienna, Austria

    G H Schernthaner

  12. Medical Clinic 3, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany

    D Wolf

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Correspondence to R Kirchmair or P Valent.

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Competing interests

EH received honoraria from Novartis. GHS received honoraria from Amgen, Astra Zeneca, Boehringer Ingelheim, BMS, Elli Lilly, Merck, Novo-Nordisk, Novartis, Pfizer and Sanofi-Aventis. DW received honoraria from Pfizer, BMS, Novartis, and Ariad and Research Grants from Pfizer and Ariad. RK received honoraria from Ariad and a Research Grant from Ariad. GH received honoraria form Novartis and Ariad. PV received honoraria from Novartis, Celgene, Pfizer, Deciphera, BMS, Ariad, and Incyte; and research grants from Novartis, Deciphera and Ariad. The remaining authors declare no conflict of interest.

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Hadzijusufovic, E., Albrecht-Schgoer, K., Huber, K. et al. Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia 31, 2388–2397 (2017). https://doi.org/10.1038/leu.2017.245

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