Inhibition of Bcr–Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells

Huang, Mei; Dorsey, Jay F.; Epling-Burnette, Pearlie K.; Nimmanapalli, Ramadevi; Landowski, Terry H.; Mora, Linda; Niu, Guilian; Sinibaldi, Dominic; Bai, Fanqi; Kraker, Alan J.; Yu, Hua; Moscinski, Lynn C.; Wei, Sheng; Djeu, Julie Y.; Dalton, William S.; Bhalla, Kapil N.; Loughran, Thomas P.; Wu, Jie; Jove, Richard

doi:10.1038/sj.onc.1206028

Cited by 120 publications

(92 citation statements)

References 73 publications

(75 reference statements)

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“…Stats are a family of cytoplasmic transcription factors that can be activated (i. showed that Stat5 expression is positively related to formation of metastatic lesions (28). Although the role of Stat5 in breast tumor progression is less clear, Stat5 phosphorylation has been implicated in the pathogenesis of chronic myelogenous leukemia (29), acute myeloid leukemia (30), and prostate cancer progression (31,32). Dephosphorylation of Stat5 is believed to be mediated by protein tyrosine phosphatases (33).…”

Section: Discussionmentioning

confidence: 99%

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Yang¹,

Yu²,

Yi³

et al. 2006

J. Proteome Res.

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Tumor metastasis is a complex multi-step process normally involving dysregulation of multiple signal transduction pathways. In this study we developed a novel approach to efficiently define dysreguated pathways associated with metastasis by comparing global gene and protein expressions of two distinct metastasis-suppressed models. Consequently, we identified common features shared by the two models which are potentially associated with metastasis.The efficiency of metastasis from the highly aggressive polyoma middle T-induced mouse mammary tumors was suppressed by either prolonged caffeine exposure or by breeding the animal to a low metastastic mouse strain. Molecular profiles of the primary tumors from both metastasis-suppressed classes were then derived to identify molecules and pathways that might underlie a common mechanism of metastasis. A number of differentially regulated genes and proteins were identified, including genes encoding basement membrane components, which were inversely related to metastatic efficiency. In addition, the analysis revealed that the Stat signal transduction pathways were potentially associated with metastasis inhibition, as demonstrated by enhanced Stat1 activation, and decreased Stat5 phosphorylation in both genetic and pharmacological modification models. Tumor cells of low-metastatic genotypes also demonstrated anti-apoptotic properties. The common changes of these pathways in all of the metastasis-suppressed systems suggest that they may be critical components in the metastatic cascade, at least in this model system. Our data demonstrate that analysis of common changes in genes and proteins in a metastatic-related context greatly decrease the complexity of data analysis, and may serve as a screening tool to identify biological important factors from large scale data.

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Section: Discussionmentioning

confidence: 99%

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Yang¹,

Yu²,

Yi³

et al. 2006

J. Proteome Res.

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“…59 The inhibition of the Bcr/Abl kinase activity by specific inhibitors blocks the constitutive Stat5 activation and growth of CML cells. 60 Interestingly, recent studies provided evidence that the Flt3 mutations are also able to activate the Stat5 pathway. The Flt3 receptor, a tyrosine kinase, is constitutively activated either by internal tandem duplication or by point mutations in 430% of AML patients.…”

Section: Il-3r In Acute Leukemiamentioning

confidence: 99%

Interleukin-3 receptor in acute leukemia

et al. 2003

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Recent studies indicate that abnormalities of the interleukin-3 receptor (IL-3R) are frequently observed in acute myeloid leukemias (AMLs) and may contribute to the proliferative advantage of leukemic blasts. This review analyzes the evidences indicating that the IL-3R represents one of the target molecules involved in the stimulation of proliferation of AMLs, and the overexpression of the IL-3Ra chain may represent one of the mechanisms contributing to the development of a highly malignant leukemic phenotype. Furthermore, there is evidence that the IL-3Ra is a marker of leukemic stem cells, at variance with normal stem cells that are IL-3Ra À . Finally, the IL-3R may represent an important target for the development of new antileukemic drugs.

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“…Electrophoretic Mobility Shift Assay Electrophoretic mobility shift assays were done as described in detail previously (11). To assess Stat5 DNAbinding activity, 8 Ag of nuclear protein extract was incubated with 32 P-radiolabeled oligonucleotide probe containing the mammary gland factor element, derived from the bovine b-casein gene promoter (5-AGATTTCTAG-GAATTCAA-3 ¶; ref.…”

Section: Immunoprecipitation and Western Blot Analysesmentioning

confidence: 99%

“…Immunoprecipitations and Western blots were done as described previously, with minor modifications (4,11). Briefly, cell lysates (500 Ag) were incubated with Abl antibody at 4jC followed by protein A/G-agarose beads (Pierce, Rockford, IL).…”

Section: Immunoprecipitation and Western Blot Analysesmentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Nam¹,

Williams

Vultur³

et al. 2007

Molecular Cancer Therapeutics

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Dasatinib (BMS-354825) is a novel, oral, potent, multitargeted kinase inhibitor of Bcr-Abl and Src family kinases (SFK) and is a promising cancer therapeutic agent. Preclinical data indicate that dasatinib is 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl, and that dasatinib is active against 18 of 19 Bcr-Abl mutations known to cause imatinib resistance. Phase I clinical data show that dasatinib is well tolerated and highly effective for the treatment of imatinib-resistant/ imatinib-intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome -positive acute lymphoblastic leukemia. However, the molecular mechanism of action of dasatinib is not fully understood. In this study, we confirm that dasatinib inhibits tyrosine phosphorylation of SFKs, including Src, Hck, and Lyn, in K562 human CML cells. Significantly, downstream signal transducer and activator of transcription 5 (Stat5) signaling is also blocked by dasatinib as shown by decreases in levels of phosphorylated Stat5 and Stat5 DNA-binding activities. In addition, dasatinib down-regulates expression of Stat5 target genes, including Bcl-x, Mcl-1, and cyclin D1. Consistent with these results, blockade of Stat5 signaling by dasatinib is accompanied by inhibition of cell proliferation and induction of apoptosis. Surprisingly, Stat5 DNA-binding activities are enhanced with increasing cell density, which is associated with resistance to apoptosis by dasatinib. Our findings indicate that inhibition of Stat5 signaling downstream of Bcr-Abl/SFKs contributes to the action of dasatinib, and, conversely, that increasing cell density up-regulates Stat5 activation and confers resistance to dasatinib. Moreover, the level of phosphorylated Stat5 in CML cells represents a mechanistically relevant biomarker for monitoring inhibition of Bcr-Abl signaling by dasatinib in CML patients using convenient immunocytochemical assays.

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Inhibition of Bcr–Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells

Cited by 120 publications

References 73 publications

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Parallel Analysis of Transcript and Translation Profiles: Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Interleukin-3 receptor in acute leukemia

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

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