Cargando…
The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling
Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We co...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628476/ https://www.ncbi.nlm.nih.gov/pubmed/37941547 http://dx.doi.org/10.3389/fonc.2023.1277453 |
_version_ | 1785131767437459456 |
---|---|
author | Olschok, Kathrin Altenburg, Bianca de Toledo, Marcelo A. S. Maurer, Angela Abels, Anne Beier, Fabian Gezer, Deniz Isfort, Susanne Paeschke, Katrin Brümmendorf, Tim H. Zenke, Martin Chatain, Nicolas Koschmieder, Steffen |
author_facet | Olschok, Kathrin Altenburg, Bianca de Toledo, Marcelo A. S. Maurer, Angela Abels, Anne Beier, Fabian Gezer, Deniz Isfort, Susanne Paeschke, Katrin Brümmendorf, Tim H. Zenke, Martin Chatain, Nicolas Koschmieder, Steffen |
author_sort | Olschok, Kathrin |
collection | PubMed |
description | Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient’s clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient’s primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1(MPL) and murine 32D(MPL) cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable. |
format | Online Article Text |
id | pubmed-10628476 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106284762023-11-08 The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling Olschok, Kathrin Altenburg, Bianca de Toledo, Marcelo A. S. Maurer, Angela Abels, Anne Beier, Fabian Gezer, Deniz Isfort, Susanne Paeschke, Katrin Brümmendorf, Tim H. Zenke, Martin Chatain, Nicolas Koschmieder, Steffen Front Oncol Oncology Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient’s clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient’s primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1(MPL) and murine 32D(MPL) cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable. Frontiers Media S.A. 2023-10-24 /pmc/articles/PMC10628476/ /pubmed/37941547 http://dx.doi.org/10.3389/fonc.2023.1277453 Text en Copyright © 2023 Olschok, Altenburg, de Toledo, Maurer, Abels, Beier, Gezer, Isfort, Paeschke, Brümmendorf, Zenke, Chatain and Koschmieder https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Olschok, Kathrin Altenburg, Bianca de Toledo, Marcelo A. S. Maurer, Angela Abels, Anne Beier, Fabian Gezer, Deniz Isfort, Susanne Paeschke, Katrin Brümmendorf, Tim H. Zenke, Martin Chatain, Nicolas Koschmieder, Steffen The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling |
title | The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling |
title_full | The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling |
title_fullStr | The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling |
title_full_unstemmed | The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling |
title_short | The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling |
title_sort | telomerase inhibitor imetelstat differentially targets jak2v617f versus calr mutant myeloproliferative neoplasm cells and inhibits jak-stat signaling |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628476/ https://www.ncbi.nlm.nih.gov/pubmed/37941547 http://dx.doi.org/10.3389/fonc.2023.1277453 |
work_keys_str_mv | AT olschokkathrin thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT altenburgbianca thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT detoledomarceloas thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT maurerangela thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT abelsanne thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT beierfabian thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT gezerdeniz thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT isfortsusanne thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT paeschkekatrin thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT brummendorftimh thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT zenkemartin thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT chatainnicolas thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT koschmiedersteffen thetelomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT olschokkathrin telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT altenburgbianca telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT detoledomarceloas telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT maurerangela telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT abelsanne telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT beierfabian telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT gezerdeniz telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT isfortsusanne telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT paeschkekatrin telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT brummendorftimh telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT zenkemartin telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT chatainnicolas telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling AT koschmiedersteffen telomeraseinhibitorimetelstatdifferentiallytargetsjak2v617fversuscalrmutantmyeloproliferativeneoplasmcellsandinhibitsjakstatsignaling |