Inhibition of STAT5: A therapeutic option in BCR-ABL1-driven leukemia

// Angelika Berger 1 , Veronika Sexl 1 , Peter Valent 2 , Richard Moriggl 3 1 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria 2 Department of Medicine I, Division of Hematology and Ludwig-Boltzmann Cluster Oncology, Medical University of Vienna, Austria 3 Ludwig-Boltzmann Institute for Cancer Research, University of Veterinary Medicine, Medical University Vienna, Austria Correspondence to: Angelika Berger, e-mail: angelika.berger@vetmeduni.ac.at Keywords: STAT5, BCR-ABL1, tyrosine kinase, leukemia, inhibitors, SH2 domain, GTPases, nuclear translocation Received: July 25, 2014      Accepted: September 06, 2014      Published: October 09, 2014 ABSTRACT The two transcription factors STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases and they fulfill all criteria of drug targets. STAT5A and STAT5B display unique nuclear shuttling mechanisms and they have a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). Moreover, STAT5A and STAT5B promote survival of leukemic stem cells. We here discuss the possibility of targeting up-stream kinases with TKI, direct STAT5 inhibition via SH2 domain obstruction and blocking nuclear translocation of STAT5. All discussed options will result in a stop of STAT5 transport to the nucleus to block STAT5-mediated transcriptional activity. In summary, recently described shuttling functions of STAT5 are discussed as potentially druggable pathways in leukemias.