Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia

被引：31

作者：

Wandler, Anica M. ^{[1
]}

Huang, Benjamin J. ^{[1
]}

Craig, Jeffrey W. ^{[2
]}

Hayes, Kathryn ^{[1
]}

Yan, Hannah ^{[1
]}

Meyer, Lauren K. ^{[1
]}

Scacchetti, Alessandro ^{[3
]}

Monsalve, Gabriela ^{[3
]}

Dail, Monique ^{[4
]}

Li, Qing ^{[5
]}

Wong, Jasmine C. ^{[1
]}

Weinberg, Olga ^{[6
]}

Hasserjian, Robert P. ^{[7
]}

Kogan, Scott C. ^{[8
]}

Jonsson, Philip ^{[9
,10
]}

Yamamoto, Keith ^{[3
]}

Sampath, Deepak ^{[4
]}

Nakitandwe, Joy ^{[11
]}

Downing, James R. ^{[11
]}

Zhang, Jinghui ^{[12
]}

Aster, Jon C. ^{[2
]}

Taylor, Barry S. ^{[9
,10
,13
]}

Shannon, Kevin ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA

[2] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[3] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

[4] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[5] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA

[6] Boston Childrens Hosp, Dept Pathol, Boston, MA USA

[7] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[8] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA

[9] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[10] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA

[11] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[12] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[13] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

来源：

LEUKEMIA | 2020年 / 34卷 / 08期

基金：

美国国家卫生研究院;

关键词：

RELAPSED CHILDHOOD; INDUCED APOPTOSIS; GENOMIC ANALYSIS; PROGNOSTIC VALUE; MEK INHIBITION; MUTATIONS; CHILDREN; PATHWAY; GENE; EFFICACY;

D O I：

10.1038/s41375-020-0748-6

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, similar to 30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or preexisting mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.

引用

页码：2025 / 2037

页数：13

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