Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells

Abstract It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-IT...

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Autores principales:	Yudong Zhang, Lingli Yuan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4a50f3ef8289495fbac690663ca81f9e
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spelling	oai:doaj.org-article:4a50f3ef8289495fbac690663ca81f9e2021-12-02T16:05:54ZFms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells10.1038/s41598-021-92566-52045-2322https://doaj.org/article/4a50f3ef8289495fbac690663ca81f9e2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92566-5https://doaj.org/toc/2045-2322Abstract It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-ITD positive AML. The overall survival rate and disease-free survival rate of AML patients with high CHK1 level were lower than those of patients with low CHK1 level. Mechanistically, FLT3-ITD recruited p300 to the CHK1 promoter and subsequently acetylated H3K27, thereby enhancing the transcription of CHK1. Interfering with the expression of CHK1 significantly inhibited the cell proliferation and induced cell apoptosis in FLT3-ITD positive MV4-11 cells. In addition, CHK1 knockdown promoted the sensitivity of MV4-11 cells to the epigenetic inhibitors JQ1 and C646. This study discovers a new therapeutic target for FLT3-ITD + AML and provided evidence for the combination of epigenetic inhibitors for AML treatment.Yudong ZhangLingli YuanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yudong Zhang Lingli Yuan Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
description	Abstract It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-ITD positive AML. The overall survival rate and disease-free survival rate of AML patients with high CHK1 level were lower than those of patients with low CHK1 level. Mechanistically, FLT3-ITD recruited p300 to the CHK1 promoter and subsequently acetylated H3K27, thereby enhancing the transcription of CHK1. Interfering with the expression of CHK1 significantly inhibited the cell proliferation and induced cell apoptosis in FLT3-ITD positive MV4-11 cells. In addition, CHK1 knockdown promoted the sensitivity of MV4-11 cells to the epigenetic inhibitors JQ1 and C646. This study discovers a new therapeutic target for FLT3-ITD + AML and provided evidence for the combination of epigenetic inhibitors for AML treatment.
format	article
author	Yudong Zhang Lingli Yuan
author_facet	Yudong Zhang Lingli Yuan
author_sort	Yudong Zhang
title	Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
title_short	Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
title_full	Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
title_fullStr	Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
title_full_unstemmed	Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
title_sort	fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4a50f3ef8289495fbac690663ca81f9e
work_keys_str_mv	AT yudongzhang fmsliketyrosinekinase3internaltandemduplicationsepigeneticallyactivatescheckpointkinase1inacutemyeloidleukemiacells AT lingliyuan fmsliketyrosinekinase3internaltandemduplicationsepigeneticallyactivatescheckpointkinase1inacutemyeloidleukemiacells
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Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells

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