PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia.
Li, J
Hlavka-Zhang, J
Shrimp, JH
Piper, C
Dupéré-Richér, D
Roth, JS
Jing, D
Casellas Román, HL
Troche, C
Swaroop, A
Kulis, M
Oyer, JA
Will, CM
Shen, M
Riva, A
Bennett, RL
Ferrando, AA
Hall, MD
Lock, RB
Licht, JD
- Publisher:
- American Association for Cancer Research (AACR)
- Publication Type:
- Journal Article
- Citation:
- Cancer Discov, 2022, 12, (1), pp. 186-203
- Issue Date:
- 2022-01
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PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia.pdf | Published version | 7.26 MB | Adobe PDF |
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Li, J | |
dc.contributor.author | Hlavka-Zhang, J | |
dc.contributor.author | Shrimp, JH | |
dc.contributor.author | Piper, C | |
dc.contributor.author | Dupéré-Richér, D | |
dc.contributor.author | Roth, JS | |
dc.contributor.author |
Jing, D https://orcid.org/0000-0002-1491-8002 |
|
dc.contributor.author | Casellas Román, HL | |
dc.contributor.author | Troche, C | |
dc.contributor.author | Swaroop, A | |
dc.contributor.author | Kulis, M | |
dc.contributor.author | Oyer, JA | |
dc.contributor.author | Will, CM | |
dc.contributor.author | Shen, M | |
dc.contributor.author | Riva, A | |
dc.contributor.author | Bennett, RL | |
dc.contributor.author | Ferrando, AA | |
dc.contributor.author | Hall, MD | |
dc.contributor.author | Lock, RB | |
dc.contributor.author | Licht, JD | |
dc.date.accessioned | 2023-04-05T04:14:51Z | |
dc.date.available | 2021-08-18 | |
dc.date.available | 2023-04-05T04:14:51Z | |
dc.date.issued | 2022-01 | |
dc.identifier.citation | Cancer Discov, 2022, 12, (1), pp. 186-203 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.issn | 2159-8290 | |
dc.identifier.uri | http://hdl.handle.net/10453/169179 | |
dc.description.abstract | Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. SIGNIFICANCE: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL.This article is highlighted in the In This Issue feature, p. 1. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | American Association for Cancer Research (AACR) | |
dc.relation.ispartof | Cancer Discov | |
dc.relation.isbasedon | 10.1158/2159-8290.CD-20-1771 | |
dc.rights | info:eu-repo/semantics/closedAccess | |
dc.subject | 1112 Oncology and Carcinogenesis | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Cell Survival | |
dc.subject.mesh | Child | |
dc.subject.mesh | Drug Resistance, Neoplasm | |
dc.subject.mesh | Enzyme Inhibitors | |
dc.subject.mesh | Female | |
dc.subject.mesh | Glucocorticoids | |
dc.subject.mesh | Histone Methyltransferases | |
dc.subject.mesh | Histone-Lysine N-Methyltransferase | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Precursor Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject.mesh | Repressor Proteins | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Histone-Lysine N-Methyltransferase | |
dc.subject.mesh | Repressor Proteins | |
dc.subject.mesh | Enzyme Inhibitors | |
dc.subject.mesh | Glucocorticoids | |
dc.subject.mesh | Cell Survival | |
dc.subject.mesh | Drug Resistance, Neoplasm | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Child | |
dc.subject.mesh | Female | |
dc.subject.mesh | Male | |
dc.subject.mesh | Precursor Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject.mesh | Histone Methyltransferases | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Cell Survival | |
dc.subject.mesh | Child | |
dc.subject.mesh | Drug Resistance, Neoplasm | |
dc.subject.mesh | Enzyme Inhibitors | |
dc.subject.mesh | Female | |
dc.subject.mesh | Glucocorticoids | |
dc.subject.mesh | Histone Methyltransferases | |
dc.subject.mesh | Histone-Lysine N-Methyltransferase | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Precursor Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject.mesh | Repressor Proteins | |
dc.title | PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia. | |
dc.type | Journal Article | |
utslib.citation.volume | 12 | |
utslib.location.activity | United States | |
utslib.for | 1112 Oncology and Carcinogenesis | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering | |
utslib.copyright.status | closed_access | * |
dc.date.updated | 2023-04-05T04:14:49Z | |
pubs.issue | 1 | |
pubs.publication-status | Published | |
pubs.volume | 12 | |
utslib.citation.issue | 1 |
Abstract:
Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. SIGNIFICANCE: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL.This article is highlighted in the In This Issue feature, p. 1.
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