Preclinical Development AZ960, a Novel Jak2 Inhibitor, Induces Growth Arrest and Apoptosis in Adult T-Cell Leukemia Cells

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 attractivemolecular target for treatment of ATL. Concomitant blockade of Jak2 and Bcl-xLmay be a promising treatment strategy for this lethal disease. Mol Cancer Ther; 9(12); 3386–95. 2010 AACR