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.
Highlights
Acute myeloid leukemia (AML), characterized by a differentiation blockage and accumulation of immature myeloid cells, has been recognized as a heterogeneous disorder in clinic [1,2]
The present study demonstrated the capacity of dasatinib to induce leukemic cell differentiation, as evidenced by the enhanced expression of CD11b, G0/G1 phase arrest and the decreased ratio of nuclear to cytoplasm in dasatinib-treated AML cells
We found that the biological function of dasatinib on inducing AML differentiation was mediated by MEK/ERK dependent activation of signal transducer and activator of transcription 1 (STAT1)
Summary
Acute myeloid leukemia (AML), characterized by a differentiation blockage and accumulation of immature myeloid cells, has been recognized as a heterogeneous disorder in clinic [1,2]. In vitro studies have shown that dasatinib significantly inhibited the growth of a variety of AML cell lines and primary blasts when treated alone or in combination with cytotoxic or molecular-targeted agents [13,14]. Lainey et al.’s study demonstrated that dasatinib by itself could overcome the AML-typical differentiation blockage as evidenced by dasatinib-induced differentiation of MOLM13 and HL60 cells [17]. This effect was further confirmed by a clinical study which provided proof of prolonged differentiation of myeloid blasts bearing the t(8;21) to mature after dasatinib treatment [18]. The mechanisms by which dasatinib trigger AML differentiation remains largely unknown
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