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Cancers
Volume 14
Issue 1
10.3390/cancers14010119
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Article

Neutrophil Extracellular Traps Are Increased in Chronic Myeloid Leukemia and Are Differentially Affected by Tyrosine Kinase Inhibitors

by
Alona Telerman
1,†,
Galit Granot
1,†,
Chiya Leibovitch
2,3,
Osnat Yarchovsky-Dolberg
2,4,
Adi Shacham-Abulafia
2,3,
Shirly Partouche
1,
Moshe Yeshurun
2,3,
Martin H. Ellis
2,4,
Pia Raanani
2,3 and
Ofir Wolach
2,3,*
1
Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Hospital, Petah-Tikva 4941492, Israel
2
Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv 39040, Israel
3
Davidoff Cancer Center, Rabin Medical Center, Institute of Hematology, Beilinson Hospital, Petah-Tikva 4941492, Israel
4
Meir Medical Center, Hematology Institute and Blood Bank, Kfar Saba 4428164, Israel
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Academic Editor: Massimo Breccia
Cancers 2022, 14(1), 119; https://doi.org/10.3390/cancers14010119
Received: 17 November 2021 / Revised: 13 December 2021 / Accepted: 24 December 2021 / Published: 27 December 2021
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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Simple Summary

Neutrophil extracellular traps (NETs) are a recently described form of neutrophil cellular death that has been associated with a thrombotic tendency in many diseases. We studied NET formation in neutrophils derived from patients with chronic myeloid leukemia (CML) and in CML neutrophil cell lines and demonstrated that NETs are increased in CML and that certain drugs used to treat CML (tyrosine kinase inhibitors—TKIs) increase NET formation. These findings may shed light on a novel mechanism linking CML, TKIs and vascular toxicity.

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. View Full-Text
Keywords: neutrophil extracellular traps; chronic myeloid leukemia; tyrosine kinase inhibitors neutrophil extracellular traps; chronic myeloid leukemia; tyrosine kinase inhibitors
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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MDPI and ACS Style

Telerman, A.; Granot, G.; Leibovitch, C.; Yarchovsky-Dolberg, O.; Shacham-Abulafia, A.; Partouche, S.; Yeshurun, M.; Ellis, M.H.; Raanani, P.; Wolach, O. Neutrophil Extracellular Traps Are Increased in Chronic Myeloid Leukemia and Are Differentially Affected by Tyrosine Kinase Inhibitors. Cancers 2022, 14, 119. https://doi.org/10.3390/cancers14010119

AMA Style

Telerman A, Granot G, Leibovitch C, Yarchovsky-Dolberg O, Shacham-Abulafia A, Partouche S, Yeshurun M, Ellis MH, Raanani P, Wolach O. Neutrophil Extracellular Traps Are Increased in Chronic Myeloid Leukemia and Are Differentially Affected by Tyrosine Kinase Inhibitors. Cancers. 2022; 14(1):119. https://doi.org/10.3390/cancers14010119

Chicago/Turabian Style

Telerman, Alona, Galit Granot, Chiya Leibovitch, Osnat Yarchovsky-Dolberg, Adi Shacham-Abulafia, Shirly Partouche, Moshe Yeshurun, Martin H. Ellis, Pia Raanani, and Ofir Wolach. 2022. "Neutrophil Extracellular Traps Are Increased in Chronic Myeloid Leukemia and Are Differentially Affected by Tyrosine Kinase Inhibitors" Cancers 14, no. 1: 119. https://doi.org/10.3390/cancers14010119

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