title: AZ960, a novel Jak2 inhibitor, induces growth arrest and apoptosis in adult T-cell leukemia cells.
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.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology* / Q000473:pathology* / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C534391:5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile; D000631:Aminopyridines; D051017:Apoptosis Regulatory Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt