title: Significance of serine threonine tyrosine kinase 1 as a drug resistance factor and therapeutic predictor in acute leukemia.
abstract: Alterations in the mRNA expression or the mutation of previously reported tyrosine kinases have been detected only in a limited number of patients with acute leukemia. In this study, we examined whether the widely expressed serine threonine tyrosine kinase 1 (STYK1)/novel oncogene with kinase domain (NOK) acts as a drug resistance factor in acute leukemia. The transfection of leukemic HL-60 cells with an STYK1 expression vector resulted in the resistance to doxorubicin and etoposide and decreased drug-induced caspase-3/7 activity and sub-G1 population. To investigate the mechanism of STYK1-induced drug resistance, microarray analysis was performed using HL-60 cells transfected with control or STYK1 expression vectors. Three tyrosine kinases (EphA4, FLT4 and STK31), two NF-κB inducers (MAPK4 and TNF-RSF11A), and two genes essential for stem cell replication (SALL4 and NOV) were identified as novel STYK1-induced genes. In addition to the data using cell line, a comparison of the leukemic patients who did and did not respond to therapy revealed that STYK1 expression before therapy was significantly higher in the non-responder group compared with the group that responded completely. These results suggest that STYK1 is a novel drug resistance factor and could be a predictor of the therapeutic response in acute leukemia.
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nirasawa
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondoh
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Kageaki
authors.initials: K
authors.lastname: Kuribayashi
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yanagihara
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D053148:Caspase 3 / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection
chemical_list: D016328:NF-kappa B; C472575:SALL4 protein, human; D014157:Transcription Factors; D004317:Doxorubicin; D020794:Receptor Protein-Tyrosine Kinases; C482299:STYK1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3