Neutrophil extracellular traps are increased in chronic myeloid leukemia and are differentially affected by tyrosine kinase inhibitors

Alona Telerman, Galit Granot, Chiya Leibovitch, Osnat Yarchovsky-Dolberg, Adi Shacham-Abulafia, Shirly Partouche, Moshe Yeshurun, Martin H. Ellis, Pia Raanani, Ofir Wolach*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiovascular complications are increasingly reported with the use of certain tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML). We studied neutrophil extracellular trap (NET) formation in CML and evaluated the effect of TKIs on NET formation. Neutrophils isolated from treatment-naïve patients with CML showed a significant increase in NET formation compared to matched controls at baseline and after stimulation with ionomycin (IO) and phorbol 12-myristate 13-acetate (PMA). Expression of citrullinated histone H3 (H3cit), peptidyl arginine deiminase 4 (PAD4) and reactive oxygen species (ROS) was significantly higher in CML samples compared to controls. Pre-treatment of neutrophils with TKIs was associated with a differential effect on NET formation, and ponatinib significantly augmented NET-associated elastase and ROS levels as compared to controls and other TKIs. BCR-ABL1 retroviral transduced HoxB8-immortalized mouse hematopoietic progenitors, which differentiate into neutrophils in-vitro, demonstrated increased H3cit & myeloperoxidase (MPO) expression consistent with excess NET formation. This was inhibited by Cl-amidine, a PAD4 inhibitor, but not by the NADPH inhibitor diphenyleneiodonium (DPI). Ponatinib pre-exposure significantly increased H3cit expression in HoxB8-BCR-ABL1 cells after stimulation with IO. In summary, CML is associated with increased NET formation, which is augmented by ponatinib, suggesting a possible role for NETs in promoting vascular toxicity in CML.

Original languageEnglish
Article number119
JournalCancers
Volume14
Issue number1
DOIs
StatePublished - 1 Jan 2022

Funding

FundersFunder number
Dotan Research Center in Hemato-Oncology

    Keywords

    • Chronic myeloid leukemia
    • Neutrophil extracellular traps
    • Tyrosine kinase inhibitors

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