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.