GILZ inhibits the mTORC2/AKT pathway in BCR-ABL+ cells

摘要: The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator transcription 5 extracellular signal-regulated 1/2. In patients with CML, inhibitors (TKIs) are used suppress kinase, resulting in impressive response rates. However, resistance can occur, especially acute-phase through various mechanisms. Here, we show that glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib dasatinib suppresses tumor growth by inactivating mammalian target rapamycin complex-2 (mTORC2)/AKT signaling pathway. mouse human models, GILZ binds mTORC2, but not mTORC1, inhibiting phosphorylation AKT (at Ser473) activating FoxO3a-mediated pro-apoptotic Bim; these results demonstrate a key inhibitor mTORC2 Furthermore, CD34(+) stem cells isolated from relapsing CML underwent apoptosis showed inhibition after incubation glucocorticoids imatinib. Our findings provide new mechanistic insights into role BCR-ABL(+) indicate regulation may influence TKI sensitivity.