Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

Erich Piovan, Jiyang Yu, Valeria Tosello, Daniel Herranz, Alberto Ambesi-Impiombato, AnaCarolina DaSilva, Marta Sanchez-Martin, Arianne Perez-Garcia, Isaura Rigo, Mireia Castillo, Stefano Indraccolo, JustinR Cross, Elisa deStanchina, Elisabeth M. Paietta, Janis Racevskis, JacobM Rowe, MartinS Tallman, Giuseppe Basso, JulesP Meijerink, Carlos Cordon-CardoAndrea Califano, AdolfoA Ferrando

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

Glucocorticoid resistance is a major driver of therapeutic failure in Tcell 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 invitro and invivo.

Original languageEnglish (US)
Pages (from-to)766-776
Number of pages11
JournalCancer Cell
Volume24
Issue number6
DOIs
StatePublished - Dec 9 2013

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Glucocorticoids
Glucocorticoid Receptors
Phosphotransferases
Therapeutics
Phosphorylation
Glucocorticoid Receptor Deficiency
Apoptosis
Gene Expression
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Piovan, E., Yu, J., Tosello, V., Herranz, D., Ambesi-Impiombato, A., DaSilva, A., ... Ferrando, A. (2013). Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. Cancer Cell, 24(6), 766-776. https://doi.org/10.1016/j.ccr.2013.10.022

Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. / Piovan, Erich; Yu, Jiyang; Tosello, Valeria; Herranz, Daniel; Ambesi-Impiombato, Alberto; DaSilva, AnaCarolina; Sanchez-Martin, Marta; Perez-Garcia, Arianne; Rigo, Isaura; Castillo, Mireia; Indraccolo, Stefano; Cross, JustinR; deStanchina, Elisa; Paietta, Elisabeth M.; Racevskis, Janis; Rowe, JacobM; Tallman, MartinS; Basso, Giuseppe; Meijerink, JulesP; Cordon-Cardo, Carlos; Califano, Andrea; Ferrando, AdolfoA.

In: Cancer Cell, Vol. 24, No. 6, 09.12.2013, p. 766-776.

Research output: Contribution to journalArticle

Piovan, E, Yu, J, Tosello, V, Herranz, D, Ambesi-Impiombato, A, DaSilva, A, Sanchez-Martin, M, Perez-Garcia, A, Rigo, I, Castillo, M, Indraccolo, S, Cross, J, deStanchina, E, Paietta, EM, Racevskis, J, Rowe, J, Tallman, M, Basso, G, Meijerink, J, Cordon-Cardo, C, Califano, A & Ferrando, A 2013, 'Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia', Cancer Cell, vol. 24, no. 6, pp. 766-776. https://doi.org/10.1016/j.ccr.2013.10.022
Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, DaSilva A et al. Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. Cancer Cell. 2013 Dec 9;24(6):766-776. https://doi.org/10.1016/j.ccr.2013.10.022
Piovan, Erich ; Yu, Jiyang ; Tosello, Valeria ; Herranz, Daniel ; Ambesi-Impiombato, Alberto ; DaSilva, AnaCarolina ; Sanchez-Martin, Marta ; Perez-Garcia, Arianne ; Rigo, Isaura ; Castillo, Mireia ; Indraccolo, Stefano ; Cross, JustinR ; deStanchina, Elisa ; Paietta, Elisabeth M. ; Racevskis, Janis ; Rowe, JacobM ; Tallman, MartinS ; Basso, Giuseppe ; Meijerink, JulesP ; Cordon-Cardo, Carlos ; Califano, Andrea ; Ferrando, AdolfoA. / Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. In: Cancer Cell. 2013 ; Vol. 24, No. 6. pp. 766-776.
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