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

被引：212

作者：

Piovan, Erich ^{[1
,2
,3
]}

Yu, Jiyang ^{[4
,5
,17
]}

Tosello, Valeria ^{[1
,6
]}

Herranz, Daniel ^{[1
]}

Ambesi-Impiombato, Alberto ^{[1
]}

Da Silva, Ana Carolina ^{[1
]}

Sanchez-Martin, Marta ^{[1
]}

Perez-Garcia, Arianne ^{[1
]}

Rigo, Isaura ^{[1
]}

Castillo, Mireia ^{[7
]}

Indraccolo, Stefano ^{[2
]}

Cross, Justin R. ^{[8
]}

de Stanchina, Elisa ^{[9
]}

Paietta, Elisabeth ^{[10
,11
]}

Racevskis, Janis ^{[10
,11
]}

Rowe, Jacob M. ^{[12
]}

Tallman, Martin S. ^{[13
]}

Basso, Giuseppe ^{[14
]}

Meijerink, Jules P. ^{[15
]}

Cordon-Cardo, Carlos ^{[7
]}

Califano, Andrea ^{[1
,4
,5
,16
,17
]}

Ferrando, Adolfo A. ^{[1
,7
,18
,19
,20
]}

机构：

[1] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA

[2] Ist Oncol Veneto IRCCS, UOC Immunol & Diagnost Mol Oncol, I-35128 Padua, Italy

[3] Univ Padua, Dipartimento Sci Chirurg Oncol & Gastroenterol, I-35128 Padua, Veneto, Italy

[4] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA

[5] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA

[6] IRCCS, Ist Oncol Veneto, I-35128 Padua, Veneto, Italy

[7] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA

[8] Mem Sloan Kettering Canc Ctr, Donald B & Catherine C Marron Canc Metab Ctr, New York, NY 10065 USA

[9] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core Facil, New York, NY 10065 USA

[10] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA

[11] Montefiore Med Ctr North Div, Dept Oncol, Bronx, NY 10466 USA

[12] Shaare Zedek Mem Hosp, Dept Hematol, IL-91031 Jerusalem, Israel

[13] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10065 USA

[14] Univ Padua, Dipartimento Salute della Donna & Bambino, I-35128 Padua, Italy

[15] Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat Oncol Hematol, Rotterdam, Netherlands

[16] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA

[17] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Canc Regulatory Network Program, New York, NY 10032 USA

[18] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Lymphoid Malignancy & Dev Program, New York, NY 10032 USA

[19] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA

[20] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA

来源：

CANCER CELL | 2013年 / 24卷 / 06期

基金：

美国国家卫生研究院;

关键词：

IN-VITRO; GENE-EXPRESSION; KEY REGULATOR; PHOSPHORYLATION; DEXAMETHASONE; ACTIVATION; APOPTOSIS; CHILDREN; BAD; INDUCTION;

D O I：

10.1016/j.ccr.2013.10.022

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 glubocorticoid 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.

引用

页码：766 / 776

页数：11

共 33 条

[1] NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity [J].

Armstrong, Florence ;

de la Grange, Philippe Brunet ;

Gerby, Bastien ;

Rouyez, Marie-Christine ;

Calvo, Julien ;

Fontenay, Michaela ;

Boissel, Nicolas ;

Dombret, Herve ;

Baruchel, Andre ;

Landman-Parker, Judith ;

Romeo, Paul-Henri ;

Ballerini, Paola ;

Pflumio, Francoise .

BLOOD, 2009, 113 (08) :1730-1740

[2] GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling [J].

Ayroldi, Emira ;

Zollo, Ornella ;

Bastianelli, Alessandra ;

Marchetti, Cristina ;

Agostini, Massimiliano ;

Di Virgilio, Rosa ;

Riccardi, Carlo .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (06) :1605-1615

[3] NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia [J].

Bandapalli, Obul R. ;

Zimmermann, Martin ;

Kox, Corinne ;

Stanulla, Martin ;

Schrappe, Martin ;

Ludwig, Wolf-Dieter ;

Koehler, Rolf ;

Muckenthaler, Martina U. ;

Kulozik, Andreas E. .

HAEMATOLOGICA, 2013, 98 (06) :928-936

[4] Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism [J].

Beesley, A. H. ;

Firth, M. J. ;

Ford, J. ;

Weller, R. E. ;

Freitas, J. R. ;

Perera, K. U. ;

Kees, U. R. .

BRITISH JOURNAL OF CANCER, 2009, 100 (12) :1926-1936

[5] Glucocorticoid resistance in paediatric acute lymphoblastic leukaemia [J].

Bhadri, Vivek A. ;

Trahair, Toby N. ;

Lock, Richard B. .

JOURNAL OF PAEDIATRICS AND CHILD HEALTH, 2012, 48 (08) :634-640

[6] Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway [J].

Bornhauser, Beat C. ;

Bonapace, Laura ;

LindholM, Dan ;

Martinez, Rodrigo ;

Cario, Gunnar ;

Schrappe, Martin ;

Niggli, Felix K. ;

Schaefer, Beat W. ;

Bourquin, Jean-Pierre .

BLOOD, 2007, 110 (06) :2084-2091

[7] Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia [J].

Chiang, Mark Y. ;

Xu, Lanwei ;

Shestova, Olga ;

Histen, Gavin ;

L'Heureux, Sarah ;

Romany, Candice ;

Childs, M. Eden ;

Gimotty, Phyllis A. ;

Aster, Jon C. ;

Pear, Warren S. .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (09) :3181-3194

[8] A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death [J].

D'Adamio, F ;

Zollo, O ;

Moraca, R ;

Ayroldi, E ;

Bruscoli, S ;

Bartoli, A ;

Cannarile, L ;

Migliorati, G ;

Riccardi, C .

IMMUNITY, 1997, 7 (06) :803-812

[9] RETRACTED: Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP) (Retracted Article) [J].

Dan, HC ;

Sun, M ;

Kaneko, S ;

Feldman, RI ;

Nicosia, SV ;

Wang, HG ;

Tsang, BK ;

Cheng, JQ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (07) :5405-5412

[10] Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery [J].

Datta, SR ;

Dudek, H ;

Tao, X ;

Masters, S ;

Fu, HA ;

Gotoh, Y ;

Greenberg, ME .

CELL, 1997, 91 (02) :231-241

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