PML / RARA inhibits expression of HSP 90 and its target AKT

Summary Essential for cell survival, the 90 kD Heat Shock Proteins ( HSP 90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP 90 is required for the stability of AKT , a serine‐threonine kinase phosphorylated in response to growth factor stimulation. AKT plays a crucial regulatory role in differentiation, cell cycle, transcription, translation, metabolism and apoptosis. Acute promyelocytic leukaemia ( APL ) is characterized by the presence of the promyelocytic leukaemia/retinoic acid receptor alpha ( PML / RARA ) fusion protein, which deregulates expression of several genes involved in differentiation and apoptosis. Here, we report inhibition of HSP 90 AA 1 and HSP 90 AB 1 isomer transcription in blasts isolated from patients with APL , associated with reduction of HSP 90 protein expression and loss of control on AKT protein phosphorylation. We show that in vitro treatment of PML / RARA expressing cells with all‐ trans retinoic acid ( ATRA ) up‐regulates HSP 90 expression and stabilizes AKT . Addition of the HSP 90‐inhibitor 17‐(allylamino)‐17‐demethoxygeldanamycin in combination with ATRA , blocks upregulation of AKT protein, indicating that HSP 90 is necessary for ATRA action on AKT . This is the first report proving that expression of HSP 90 isomers are directly and differentially repressed by PML / RARA , with critical results on cellular homeostasis of target proteins, such as AKT , in APL blasts.