Abstract
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease in which the Jak2/Stat5 pathway is constitutively activated. This study found that AZ960, a novel inhibitor of Jak2 kinase, effectively induced growth arrest and apoptosis of human T-cell lymphotropic virus type 1, HTLV-1-infected T cells (MT-1 and MT-2) in parallel with downregulation of the phosphorylated forms of Jak2 and Bcl-2 family proteins including Bcl-2 and Mcl-1. Interestingly, AZ960 increased levels of Bcl-xL in MT-1 and MT-2 cells in association with accumulation of cAMP response element-binding protein bound to the Bcl-xL promoter as measured by chromatin immunoprecipitation assay. Importantly, genetic inhibition of Bcl-xL by a small interfering RNA potentiated antiproliferative effects of AZ960 in MT-1 cells. Taken together, Jak2 is an attractive molecular target for treatment of ATL. Concomitant blockade of Jak2 and Bcl-xL may be a promising treatment strategy for this lethal disease.
©2010 AACR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / metabolism
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Separation
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Cyclic AMP Response Element-Binding Protein / metabolism
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Down-Regulation / drug effects
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Human T-lymphotropic virus 1 / drug effects
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Humans
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / metabolism
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Leukemia-Lymphoma, Adult T-Cell / enzymology*
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Leukemia-Lymphoma, Adult T-Cell / pathology*
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Leukemia-Lymphoma, Adult T-Cell / virology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphotyrosine / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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RNA, Small Interfering / metabolism
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STAT3 Transcription Factor / metabolism
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STAT5 Transcription Factor / metabolism
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Signal Transduction / drug effects
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T-Lymphocytes / drug effects
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T-Lymphocytes / enzymology
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T-Lymphocytes / virology
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bcl-X Protein / metabolism
Substances
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5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile
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Aminopyridines
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Apoptosis Regulatory Proteins
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Cyclic AMP Response Element-Binding Protein
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Protein Kinase Inhibitors
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Pyrazoles
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RNA, Small Interfering
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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bcl-X Protein
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Phosphotyrosine
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Phosphatidylinositol 3-Kinases
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Janus Kinase 2
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Proto-Oncogene Proteins c-akt