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

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.

Ubiquitin‐activating enzyme E1 inhibitor PYR41 attenuates angiotensin II‐induced activation of dendritic cells via the IκBa/NF‐κB and MKP1/ERK/STAT1 pathways

“…Several signalling pathways are known to play critical roles in regulating the maturation and activation of DCs, including NF‐ κ B, MAPKs and STAT1 . For examples, NF‐ κ B coordinately regulates the phenotypic and functional maturation .…”

“…For examples, NF‐ κ B coordinately regulates the phenotypic and functional maturation . STAT1 signalling is required for phenotypic maturation and T helper type 1 cell priming of mouse BMDCs, and the phosphorylation of STAT1 requires the activation of MAPK kinase/ERK cascades in human acute myeloid leukaemia cells and macrophages . Recently, studies indicate that Ang II stimulation results in activation of ERK, but not p38 MAPK and JNK in mouse BMDCs, whereas in human monocyte‐derived DCs, Ang II activates ERK, p38 and NF‐ κ B, but not JNK .…”

“…Several signalling pathways are known to play critical roles in regulating the maturation and activation of DCs, including NF-jB, MAPKs and STAT1. 20,21,[37][38][39][40] For examples, NF-jB coordinately regulates the phenotypic and 170 000 130 000 100 000 70 000 55 000 170 000 130 000 100 000 70 000 55 000 functional maturation. 20 STAT1 signalling is required for phenotypic maturation and T helper type 1 cell priming of mouse BMDCs, 22,23 and the phosphorylation of STAT1 requires the activation of MAPK kinase/ERK cascades in human acute myeloid leukaemia cells and macrophages.…”

Dasatinib Accelerates Valproic Acid-Induced Acute Myeloid Leukemia Cell Death by Regulation of Differentiation Capacity

“…It has also been found to induce myeloblast differentiation [22]. Moreover, dasatinib in combination with retinoic acid has been shown to promote AML differentiation [2], [21] and to greatly increase the expression of differentiation marker CD11b.…”

Retinoid Chemoprevention: Who Can Benefit?

“…Another clinical trial, NCT00892190 “Study of Dasatinib and All-Trans Retinoic Acid for Relapsed/Refractory and/or Elderly Patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)”, is also recruiting patients. We and others have provided evidence that combination therapy of retinoic acid plus SFK inhibitors targets critical cytosolic signaling components, and this could be of therapeutic benefit [33••, 63]. Another proposed combination therapy with ATRA in non-APL AML patients uses ATRA with valproic acid.…”