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

Erich Piovan; Jiyang Yu; Valeria Tosello; Daniel Herranz; Alberto Ambesi-Impiombato; Ana Carolina DaSilva; Marta Sanchez-Martin; Arianne Perez-Garcia; Isaura Rigo; Mireia Castillo; Stefano Indraccolo; Justin R. Cross; Elisa deStanchina; Elisabeth Paietta; Janis Racevskis; Jacob M. Rowe; Martin S. Tallman; Giuseppe Basso; Jules P. Meijerink; Carlos Cordon-Cardo; Andrea Califano; Adolfo A. 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, Ana Carolina DaSilva, Marta Sanchez-Martin, Arianne Perez-Garcia, Isaura Rigo, Mireia Castillo, Stefano Indraccolo, Justin R. Cross, Elisa deStanchina, Elisabeth Paietta, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Giuseppe Basso, Jules P. Meijerink, Carlos Cordon-CardoAndrea Califano^*, Adolfo A. Ferrando

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

213 Scopus citations

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 (US)
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
State	Published - Dec 9 2013

Funding

This work was supported by the National Institutes of Health (grants R01CA129382 to A.A.F., U24 CA114737 to E.P., RC2 CA148308 to A.C. and A.F., and U54CA121852 to A.C.), the Stand Up To Cancer Innovative Research Award (to A.A.F.), the Chemotherapy Foundation (to A.A.F.), the Leukemia & Lymphoma Society Scholar Award (to A.A.F.), a Leukemia & Lymphoma Society SCOR Grant (to A.A.F.), and the ECOG Leukemia Tissue Bank. We are grateful to A. Kung for the FUW-luc vector, J. Aster for the MigR1- NOTCH1 L1601PΔP vector, P.P. Pandolfi for the Pten f conditional knockout mouse, T. Ludwig for the ROSA26 Cre-ERT2/+ mouse, S. Minuzzo for generation of T-ALL xenografts, L. Xu for help in animal procedures, M.A. Gawinowicz from the Proteomics Share Resource at the Herbert Irving Comprehensive Cancer Center at Columbia University for assistance in mass spectrometry analysis, and R. Baer for helpful discussions and revision of the manuscript.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2013.10.022

Cite this

Piovan, E., Yu, J., Tosello, V., Herranz, D., Ambesi-Impiombato, A., DaSilva, A. C., Sanchez-Martin, M., Perez-Garcia, A., Rigo, I., Castillo, M., Indraccolo, S., Cross, J. R., deStanchina, E., Paietta, E., Racevskis, J., Rowe, J. M., Tallman, M. S., Basso, G., Meijerink, J. P., ... Ferrando, A. 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

@article{640d7ae72fdc44b6bc74d45cb76bb022,

title = "Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia",

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 DaSilva, {Ana Carolina} and Marta Sanchez-Martin and Arianne Perez-Garcia and Isaura Rigo and Mireia Castillo and Stefano Indraccolo and Cross, {Justin R.} and Elisa deStanchina and Elisabeth Paietta and Janis Racevskis and Rowe, {Jacob M.} and Tallman, {Martin S.} and Giuseppe Basso and Meijerink, {Jules P.} and Carlos Cordon-Cardo and Andrea Califano and Ferrando, {Adolfo A.}",

note = "Funding Information: This work was supported by the National Institutes of Health (grants R01CA129382 to A.A.F., U24 CA114737 to E.P., RC2 CA148308 to A.C. and A.F., and U54CA121852 to A.C.), the Stand Up To Cancer Innovative Research Award (to A.A.F.), the Chemotherapy Foundation (to A.A.F.), the Leukemia & Lymphoma Society Scholar Award (to A.A.F.), a Leukemia & Lymphoma Society SCOR Grant (to A.A.F.), and the ECOG Leukemia Tissue Bank. We are grateful to A. Kung for the FUW-luc vector, J. Aster for the MigR1- NOTCH1 L1601PΔP vector, P.P. Pandolfi for the Pten f conditional knockout mouse, T. Ludwig for the ROSA26 Cre-ERT2/+ mouse, S. Minuzzo for generation of T-ALL xenografts, L. Xu for help in animal procedures, M.A. Gawinowicz from the Proteomics Share Resource at the Herbert Irving Comprehensive Cancer Center at Columbia University for assistance in mass spectrometry analysis, and R. Baer for helpful discussions and revision of the manuscript. ",

year = "2013",

month = dec,

day = "9",

doi = "10.1016/j.ccr.2013.10.022",

language = "English (US)",

volume = "24",

pages = "766--776",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

Piovan, E, Yu, J, Tosello, V, Herranz, D, Ambesi-Impiombato, A, DaSilva, AC, Sanchez-Martin, M, Perez-Garcia, A, Rigo, I, Castillo, M, Indraccolo, S, Cross, JR, deStanchina, E, Paietta, E, Racevskis, J, Rowe, JM, Tallman, MS, Basso, G, Meijerink, JP, Cordon-Cardo, C, Califano, A & Ferrando, AA 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

TY - JOUR

T1 - Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

AU - Piovan, Erich

AU - Yu, Jiyang

AU - Tosello, Valeria

AU - Herranz, Daniel

AU - Ambesi-Impiombato, Alberto

AU - DaSilva, Ana Carolina

AU - Sanchez-Martin, Marta

AU - Perez-Garcia, Arianne

AU - Rigo, Isaura

AU - Castillo, Mireia

AU - Indraccolo, Stefano

AU - Cross, Justin R.

AU - deStanchina, Elisa

AU - Paietta, Elisabeth

AU - Racevskis, Janis

AU - Rowe, Jacob M.

AU - Tallman, Martin S.

AU - Basso, Giuseppe

AU - Meijerink, Jules P.

AU - Cordon-Cardo, Carlos

AU - Califano, Andrea

AU - Ferrando, Adolfo A.

N1 - Funding Information: This work was supported by the National Institutes of Health (grants R01CA129382 to A.A.F., U24 CA114737 to E.P., RC2 CA148308 to A.C. and A.F., and U54CA121852 to A.C.), the Stand Up To Cancer Innovative Research Award (to A.A.F.), the Chemotherapy Foundation (to A.A.F.), the Leukemia & Lymphoma Society Scholar Award (to A.A.F.), a Leukemia & Lymphoma Society SCOR Grant (to A.A.F.), and the ECOG Leukemia Tissue Bank. We are grateful to A. Kung for the FUW-luc vector, J. Aster for the MigR1- NOTCH1 L1601PΔP vector, P.P. Pandolfi for the Pten f conditional knockout mouse, T. Ludwig for the ROSA26 Cre-ERT2/+ mouse, S. Minuzzo for generation of T-ALL xenografts, L. Xu for help in animal procedures, M.A. Gawinowicz from the Proteomics Share Resource at the Herbert Irving Comprehensive Cancer Center at Columbia University for assistance in mass spectrometry analysis, and R. Baer for helpful discussions and revision of the manuscript.

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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U2 - 10.1016/j.ccr.2013.10.022

DO - 10.1016/j.ccr.2013.10.022

M3 - Article

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AN - SCOPUS:84891913160

SN - 1535-6108

VL - 24

SP - 766

EP - 776

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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