Cargando…
Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors
Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were managea...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555816/ https://www.ncbi.nlm.nih.gov/pubmed/32911605 http://dx.doi.org/10.3390/ijms21186550 |
_version_ | 1783594095618293760 |
---|---|
author | Baerlocher, Gabriela M. Rusbuldt, Joshua Bussolari, Jacqueline Huang, Fei |
author_facet | Baerlocher, Gabriela M. Rusbuldt, Joshua Bussolari, Jacqueline Huang, Fei |
author_sort | Baerlocher, Gabriela M. |
collection | PubMed |
description | Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins that recognize pathogen-associated molecular patterns and stimulate innate immune and pro-apoptotic responses. Because imetelstat is an oligonucleotide, and some oligonucleotides can activate TLRs, we conducted an in vitro study to rule out the possibility of imetelstat-associated thrombocytopenia by off-target effects through activation of TLRs. We used HEK293 cell lines stably co-expressing a human TLR gene and an NFκB-inducible reporter to investigate whether imetelstat can activate TLR signaling. We treated the cells with imetelstat or control oligonucleotides for 20 h, and used absorbance of the culture media to calculate the reporter activity. Treatment with imetelstat within or beyond the clinically relevant concentrations had no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9. This result was not surprising since the structure of imetelstat does not meet the reported minimal structural requirements for TLR9 activation. Furthermore, imetelstat treatment of the MPN cell line HEL did not impact the expression of TLR signaling pathway target genes that are commonly induced by activation of different TLRs, whereas it significantly reduced its target gene hTERT, human telomerase reverse transcriptase, in a dose- and time-dependent manner. Hence, cytopenias, especially thrombocytopenia observed in some patients treated with imetelstat, are not mediated by off-target interactions with TLRs. |
format | Online Article Text |
id | pubmed-7555816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75558162020-10-19 Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors Baerlocher, Gabriela M. Rusbuldt, Joshua Bussolari, Jacqueline Huang, Fei Int J Mol Sci Communication Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins that recognize pathogen-associated molecular patterns and stimulate innate immune and pro-apoptotic responses. Because imetelstat is an oligonucleotide, and some oligonucleotides can activate TLRs, we conducted an in vitro study to rule out the possibility of imetelstat-associated thrombocytopenia by off-target effects through activation of TLRs. We used HEK293 cell lines stably co-expressing a human TLR gene and an NFκB-inducible reporter to investigate whether imetelstat can activate TLR signaling. We treated the cells with imetelstat or control oligonucleotides for 20 h, and used absorbance of the culture media to calculate the reporter activity. Treatment with imetelstat within or beyond the clinically relevant concentrations had no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9. This result was not surprising since the structure of imetelstat does not meet the reported minimal structural requirements for TLR9 activation. Furthermore, imetelstat treatment of the MPN cell line HEL did not impact the expression of TLR signaling pathway target genes that are commonly induced by activation of different TLRs, whereas it significantly reduced its target gene hTERT, human telomerase reverse transcriptase, in a dose- and time-dependent manner. Hence, cytopenias, especially thrombocytopenia observed in some patients treated with imetelstat, are not mediated by off-target interactions with TLRs. MDPI 2020-09-08 /pmc/articles/PMC7555816/ /pubmed/32911605 http://dx.doi.org/10.3390/ijms21186550 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Baerlocher, Gabriela M. Rusbuldt, Joshua Bussolari, Jacqueline Huang, Fei Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors |
title | Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors |
title_full | Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors |
title_fullStr | Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors |
title_full_unstemmed | Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors |
title_short | Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors |
title_sort | myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555816/ https://www.ncbi.nlm.nih.gov/pubmed/32911605 http://dx.doi.org/10.3390/ijms21186550 |
work_keys_str_mv | AT baerlochergabrielam myelosuppressioninpatientstreatedwiththetelomeraseinhibitorimetelstatisnotmediatedthroughactivationoftolllikereceptors AT rusbuldtjoshua myelosuppressioninpatientstreatedwiththetelomeraseinhibitorimetelstatisnotmediatedthroughactivationoftolllikereceptors AT bussolarijacqueline myelosuppressioninpatientstreatedwiththetelomeraseinhibitorimetelstatisnotmediatedthroughactivationoftolllikereceptors AT huangfei myelosuppressioninpatientstreatedwiththetelomeraseinhibitorimetelstatisnotmediatedthroughactivationoftolllikereceptors |