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 Paietta; Janis Racevskis; JacobM Rowe; MartinS Tallman; Giuseppe Basso; JulesP Meijerink; Carlos Cordon-Cardo; Andrea Califano; AdolfoA Ferrando

doi:10.1016/j.ccr.2013.10.022

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 Paietta, Janis Racevskis, JacobM Rowe, MartinS Tallman, Giuseppe Basso, JulesP Meijerink, Carlos Cordon-CardoAndrea Califano, AdolfoA Ferrando

Istituto Oncologico Veneto

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	766-776
Number of pages	11
Journal	Cancer Cell
Volume	24
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2013.10.022
Publication status	Published - Dec 9 2013

ASJC Scopus subject areas

Cancer Research
Cell Biology
Oncology

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10.1016/j.ccr.2013.10.022

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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, E., Racevskis, J., Rowe, J., Tallman, M., Basso, G., Meijerink, J., ... 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

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, E, 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

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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.",

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

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AU - Piovan, Erich

AU - Yu, Jiyang

AU - Tosello, Valeria

AU - Herranz, Daniel

AU - Ambesi-Impiombato, Alberto

AU - DaSilva, AnaCarolina

AU - Sanchez-Martin, Marta

AU - Perez-Garcia, Arianne

AU - Rigo, Isaura

AU - Castillo, Mireia

AU - Indraccolo, Stefano

AU - Cross, JustinR

AU - deStanchina, Elisa

AU - Paietta, Elisabeth

AU - Racevskis, Janis

AU - Rowe, JacobM

AU - Tallman, MartinS

AU - Basso, Giuseppe

AU - Meijerink, JulesP

AU - Cordon-Cardo, Carlos

AU - Califano, Andrea

AU - Ferrando, AdolfoA

PY - 2013/12/9

Y1 - 2013/12/9

N2 - 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.

AB - 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.

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

Abstract

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