Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Rintaro Hashizume; Noemi Andor; Yuichiro Ihara; Robin Lerner; Haiyun Gan; Xiaoyue Chen; Dong Fang; Xi Huang; Maxwell W. Tom; Vy Ngo; David Solomon; Sabine Mueller; Pamela L. Paris; Zhiguo Zhang; Claudia Petritsch; Nalin Gupta; Todd A. Waldman; C. David James

doi:10.1038/nm.3716

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Rintaro Hashizume, Noemi Andor, Yuichiro Ihara, Robin Lerner, Haiyun Gan, Xiaoyue Chen, Dong Fang, Xi Huang, Maxwell W. Tom, Vy Ngo, David Solomon, Sabine Mueller, Pamela L. Paris, Zhiguo Zhang, Claudia Petritsch, Nalin Gupta, Todd A. Waldman, C. David James

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

281 Scopus citations

Abstract

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

Original language	English (US)
Pages (from-to)	1394-1396
Number of pages	3
Journal	Nature Medicine
Volume	20
Issue number	12
DOIs	https://doi.org/10.1038/nm.3716
State	Published - Dec 1 2014

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Hashizume, R., Andor, N., Ihara, Y., Lerner, R., Gan, H., Chen, X., Fang, D., Huang, X., Tom, M. W., Ngo, V., Solomon, D., Mueller, S., Paris, P. L., Zhang, Z., Petritsch, C., Gupta, N., Waldman, T. A., & James, C. D. (2014). Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nature Medicine, 20(12), 1394-1396. https://doi.org/10.1038/nm.3716

Hashizume, R, Andor, N, Ihara, Y, Lerner, R, Gan, H, Chen, X, Fang, D, Huang, X, Tom, MW, Ngo, V, Solomon, D, Mueller, S, Paris, PL, Zhang, Z, Petritsch, C, Gupta, N, Waldman, TA & James, CD 2014, 'Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma', Nature Medicine, vol. 20, no. 12, pp. 1394-1396. https://doi.org/10.1038/nm.3716

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title = "Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma",

abstract = "Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.",

author = "Rintaro Hashizume and Noemi Andor and Yuichiro Ihara and Robin Lerner and Haiyun Gan and Xiaoyue Chen and Dong Fang and Xi Huang and Tom, {Maxwell W.} and Vy Ngo and David Solomon and Sabine Mueller and Paris, {Pamela L.} and Zhiguo Zhang and Claudia Petritsch and Nalin Gupta and Waldman, {Todd A.} and James, {C. David}",

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doi = "10.1038/nm.3716",

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AU - Hashizume, Rintaro

AU - Andor, Noemi

AU - Ihara, Yuichiro

AU - Lerner, Robin

AU - Gan, Haiyun

AU - Chen, Xiaoyue

AU - Fang, Dong

AU - Huang, Xi

AU - Tom, Maxwell W.

AU - Ngo, Vy

AU - Solomon, David

AU - Mueller, Sabine

AU - Paris, Pamela L.

AU - Zhang, Zhiguo

AU - Petritsch, Claudia

AU - Gupta, Nalin

AU - Waldman, Todd A.

AU - James, C. David

PY - 2014/12/1

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N2 - Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

AB - Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

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Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Abstract

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