Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia Academic Article uri icon

Overview

MeSH Major

  • Dexamethasone
  • Heterocyclic Compounds, 3-Ring
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Proto-Oncogene Proteins c-akt

abstract

  • Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.

publication date

  • December 9, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3878658

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2013.10.022

PubMed ID

  • 24291004

Additional Document Info

start page

  • 766

end page

  • 76

volume

  • 24

number

  • 6