Akt2 mediates glucocorticoid resistance in lymphoid malignancies through FoxO3a/Bim axis and serves as a direct target for resistance reversal.

ABSTRACT: Glucocorticoids (GCs) are widely used drugs in the treatment of lymphoid malignancies; resistance of GCs in lymphocytes confers poor prognosis and the mechanisms are poorly understood. Here, we found T-acute lymphoblastic leukemia (T-ALL) cells acquire resistance to dexamethasone (DEX)-mediated killing through abnormal activation of Akt, resulting in inhibition of the FoxO3a/Bim pathway. The resistant state was reported to be associated with increased glycolysis, NOTCH1 activating mutations and activated PI3K/ serum GS regulated kinases (SGK) pathway. Use of aforementioned pathway inhibitors blocked FoxO3a-phosphorylation and partially improved DEX-mediated killing of GC-resistant T-ALL cells, further revealing the essential role of the FoxO3a/Bim pathway in the development of GC resistanc

SUBMITTER: Xie M 

PROVIDER: S-EPMC6312545 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature