American Association for Cancer Research
21598290cd201771-sup-256881_2_supp_7316575_qxsvh2.pdf (24.68 MB)

Supplementary Methods and Figures from PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia

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journal contribution
posted on 2023-04-03, 23:43 authored by 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

Supplementary Methods and Figures


Leukemia and Lymphoma Society Specialized Center of Excellence Grant

Leukemia and Lymphoma Society Special Fellow Grants

Rally Foundation for Childhood Cancer Research

Bear Necessities Pediatric Cancer Foundation

Cancer Australia and The Kids' Cancer Project Grant

National Health and Medical Research Council of Australia NHMRC Fellowships

Cancer Institute NSW Early Career Fellowship



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. 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