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

Autor:	Li J; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Hlavka-Zhang J; Children's Cancer Institute, School of Women's and Children's Health, University of New South Wales Sydney, Sydney, Australia., Shrimp JH; National Center for Advancing Translational Sciences, NIH, Rockville, Maryland., Piper C; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Dupéré-Richér D; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Roth JS; National Center for Advancing Translational Sciences, NIH, Rockville, Maryland., Jing D; Children's Cancer Institute, School of Women's and Children's Health, University of New South Wales Sydney, Sydney, Australia., Casellas Román HL; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Troche C; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Swaroop A; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Kulis M; Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain., Oyer JA; Pfizer Inc., Oncology Research and Development, San Diego, California., Will CM; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Shen M; National Center for Advancing Translational Sciences, NIH, Rockville, Maryland., Riva A; Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, Florida., Bennett RL; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida., Ferrando AA; Institute of Cancer Genetics, Columbia University, New York, New York., Hall MD; National Center for Advancing Translational Sciences, NIH, Rockville, Maryland., Lock RB; Children's Cancer Institute, School of Women's and Children's Health, University of New South Wales Sydney, Sydney, Australia., Licht JD; Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, Florida. jdlicht@ufl.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2022 Jan; Vol. 12 (1), pp. 186-203. Date of Electronic Publication: 2021 Aug 20.
DOI:	10.1158/2159-8290.CD-20-1771
Abstrakt:	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 . (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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