Nilotinib-induced alterations in endothelial cell function recapitulate clinical vascular phenotypes independent of ABL1

Emily A. Pinheiro, Jean Marc DeKeyser, Brian Lenny, Yadav Sapkota, Paul W. Burridge*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Nilotinib is a highly effective treatment for chronic myeloid leukemia but has been consistently associated with the development of nilotinib-induced arterial disease (NAD) in a subset of patients. To date, which cell types mediate this effect and whether NAD results from on-target mechanisms is unknown. We utilized human induced pluripotent stem cells (hiPSCs) to generate endothelial cells and vascular smooth muscle cells for in vitro study of NAD. We found that nilotinib adversely affects endothelial proliferation and migration, in addition to increasing intracellular nitric oxide. Nilotinib did not alter endothelial barrier function or lipid uptake. No effect of nilotinib was observed in vascular smooth muscle cells, suggesting that NAD is primarily mediated through endothelial cells. To evaluate whether NAD results from enhanced inhibition of ABL1, we generated multiple ABL1 knockout lines. The effects of nilotinib remained unchanged in the absence of ABL1, suggesting that NAD results from off- rather than on-target signaling. The model established in the present study can be applied to future mechanistic and patient-specific pharmacogenomic studies.

Original languageEnglish (US)
Article number7123
JournalScientific reports
Volume14
Issue number1
DOIs
StatePublished - Dec 2024

Funding

This work was supported by National Institutes of Health [R01 CA220002 and CA261898 to P.W.B., F31 HL151160 to E.A.P., S10-OD026867]; and the Leducq Foundation [P.W.B.].

ASJC Scopus subject areas

  • General

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