About: MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia

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About: MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia
Creator	Yang, Bo Fang, Yanfen He, Qiaojun Jing, Hui Lin, Meihua »more»
source	PMC
abstract	Dasatinib (BMS-354825) is a FDA-approved multitargeted kinase inhibitor of BCR/ABL and Src kinases. It is now used in the treatment of chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapies, including imatinib. Here we report a novel effect of dasatinib on inducing the differentiation of acute myeloid leukemia (AML) cells through MEK/ERK-dependent activation of signal transducer and activator of transcription 1 (STAT1). We found that dasatinib could induce the differentiation of AML cells as demonstrated by the expression of differentiation marker CD11b, G0/G1 phase arrest and decreased ratio of nucleus to cytoplasm. Of note, dasatinib induced robust phosphorylation of STAT1 both at Tyr701 and Ser727 as well as the redistribution of STAT1 from the cytoplasm to the nucleus, thus leading to the transcription of STAT1-targeted genes. Knocking down STAT1 expression by shRNA significantly attenuated dasatinib-induced differentiation, indicating an important role of STAT1 in myeloid maturation. We further found that dasatinib-induced activation of STAT1 was regulated by the MEK/ERK kinases. The phosporylation of MEK and ERK occurred rapidly upon dasatinib treatment and increased progressively as differentiation was induced. MEK inhibitors PD98059 and U0216 not only inhibited the phosphorylation of STAT1, but also abrogated dasatinib-induced myeloid differentiation, suggesting that MEK/ERK dependent phosphorylation of STAT1 might be indispensable for the differentiating effect of dasatinib in AML cells. Taken together, our study suggests that STAT1 is an important mediator in dasatinib-induced differentiation of AML cells, whose activation requires the activation of MEK/ERK cascades.
has issue date	2013-06-25(xsd:dateTime)
bibo:doi	10.1371/journal.pone.0066915
bibo:pmid	23825585
has license	cc-by
sha1sum (hex)	7f3e18a9a954832a2335fa3c26c42f127a79855c
schema:url	https://doi.org/10.1371/journal.pone.0066915
resource representing a document's title	MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia
has PubMed Central identifier	PMC3692534
has PubMed identifier	23825585
schema:publication	PLoS One
resource representing a document's body	covid:7f3e18a9a954832a2335fa3c26c42f127a79855c#body_text
is schema:about of	named entity 'The' named entity 'cells' named entity 'STAT1' named entity 'acute myeloid leukemia' named entity 'induce' »more»

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