STAT5 as a CML target: STATinib therapies?

摘要

In this issue of Blood, Nelson and colleagues1 and Warsch and colleagues2 report that signal transducers and activators of transcription 5 (STAT5) is an attractive target to circumvent tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML).BCR-ABL activate many signaling pathways in leukemic cells, such as RAS,PI-3K and NF-kappaB. STAT5 was one of the first pathways to be described as being consti-tutively activated by p210 BCR-ABL and pl90 BCR-ABL. STAT5 activation has been shown to be correlated with functional effects such as antiapoptosis through activation of Bcl-XL and drug resistance phenotype through activation of Rad51. BCR-ABL directly induces a tyrosine-phosphorylation and dimerization of STATS followed by nuclear translocation of the STATS dimers that then bind to consensus sequences through their DNA binding domain and promote activation of downstream target genes (see figure).