PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia

Jianping Li, Julia Hlavka Zhang, Jonathan H. Shrimp, Crissandra Piper, Daphne Dupéré Richér, Jacob S. Roth, Duohui Jing, Heidi L. Casellas Román, Catalina Troche, Alok Swaroop, Marta Kulis, Jon A. Oyer, Christine M. Will, Min Shen, Alberto Riva, Richard L. Bennett, Adolfo A. Ferrando, Matthew D. Hall, Richard B. Lock, Jonathan D. Licht

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish
Pages (from-to)186-203
Number of pages18
JournalCancer Discovery
Volume12
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

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