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MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia

The somatic mutation of FLT3 occurs in 30% of acute myeloid leukemia (AML), with the majority of mutations exhibiting internal tandem duplication (ITD). On the other hand, the induction of telomerase reverse transcriptase (hTERT) and the activation of telomerase is a key step in AML development. Her...

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Autores principales: Zhang, Xiaolu, Li, Bingnan, Yu, Jingya, Dahlström, Jenny, Tran, Anh Nhi, Björkhom, Magnus, Xu, Dawei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748426/
https://www.ncbi.nlm.nih.gov/pubmed/29080039
http://dx.doi.org/10.1007/s00277-017-3158-8
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author Zhang, Xiaolu
Li, Bingnan
Yu, Jingya
Dahlström, Jenny
Tran, Anh Nhi
Björkhom, Magnus
Xu, Dawei
author_facet Zhang, Xiaolu
Li, Bingnan
Yu, Jingya
Dahlström, Jenny
Tran, Anh Nhi
Björkhom, Magnus
Xu, Dawei
author_sort Zhang, Xiaolu
collection PubMed
description The somatic mutation of FLT3 occurs in 30% of acute myeloid leukemia (AML), with the majority of mutations exhibiting internal tandem duplication (ITD). On the other hand, the induction of telomerase reverse transcriptase (hTERT) and the activation of telomerase is a key step in AML development. Here, we sought to determine whether FLT3ITD regulates hTERT expression in AML cells and whether hTERT expression affects FLT3 inhibitors’ therapeutic efficacy on AML. FLT3ITD-harboring AML cell lines and primary cells treated with the FLT3 inhibitor PKC412 displayed a rapid decline in the levels of hTERT mRNA and telomerase activity. Moreover, PKC412 inhibited hTERT gene transcription in a c-MYC-dependent manner. The ectopic expression of hTERT significantly attenuated the apoptotic effect of PKC412 on AML cells. Mechanistically, hTERT enhanced the activity of FLT3 downstream effectors or alternative RTK signaling, thereby enhancing AKT phosphorylation, in AML cells treated with PKC412. Collectively, PKC412 downregulates hTERT expression and telomerase activity in a MYC-dependent manner and this effect is required for its optimal anti-AML efficacy, while hTERT over-expression confers AML cells resistance to a targeted therapeutic agent PKC412. These findings suggest that the functional interplay between FLT3ITD and hTERT contributes to the AML pathogenesis and interferes with the efficacy of FLT3ITD-targeted therapy.
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spelling pubmed-57484262018-01-19 MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia Zhang, Xiaolu Li, Bingnan Yu, Jingya Dahlström, Jenny Tran, Anh Nhi Björkhom, Magnus Xu, Dawei Ann Hematol Original Article The somatic mutation of FLT3 occurs in 30% of acute myeloid leukemia (AML), with the majority of mutations exhibiting internal tandem duplication (ITD). On the other hand, the induction of telomerase reverse transcriptase (hTERT) and the activation of telomerase is a key step in AML development. Here, we sought to determine whether FLT3ITD regulates hTERT expression in AML cells and whether hTERT expression affects FLT3 inhibitors’ therapeutic efficacy on AML. FLT3ITD-harboring AML cell lines and primary cells treated with the FLT3 inhibitor PKC412 displayed a rapid decline in the levels of hTERT mRNA and telomerase activity. Moreover, PKC412 inhibited hTERT gene transcription in a c-MYC-dependent manner. The ectopic expression of hTERT significantly attenuated the apoptotic effect of PKC412 on AML cells. Mechanistically, hTERT enhanced the activity of FLT3 downstream effectors or alternative RTK signaling, thereby enhancing AKT phosphorylation, in AML cells treated with PKC412. Collectively, PKC412 downregulates hTERT expression and telomerase activity in a MYC-dependent manner and this effect is required for its optimal anti-AML efficacy, while hTERT over-expression confers AML cells resistance to a targeted therapeutic agent PKC412. These findings suggest that the functional interplay between FLT3ITD and hTERT contributes to the AML pathogenesis and interferes with the efficacy of FLT3ITD-targeted therapy. Springer Berlin Heidelberg 2017-10-27 2018 /pmc/articles/PMC5748426/ /pubmed/29080039 http://dx.doi.org/10.1007/s00277-017-3158-8 Text en © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Zhang, Xiaolu
Li, Bingnan
Yu, Jingya
Dahlström, Jenny
Tran, Anh Nhi
Björkhom, Magnus
Xu, Dawei
MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
title MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
title_full MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
title_fullStr MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
title_full_unstemmed MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
title_short MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
title_sort myc-dependent downregulation of telomerase by flt3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748426/
https://www.ncbi.nlm.nih.gov/pubmed/29080039
http://dx.doi.org/10.1007/s00277-017-3158-8
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