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

^*Corresponding author for this work

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

343 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

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.3716

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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

@article{fe152c548ace4692b445fbbb15cdba0f,

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}",

note = "Funding Information: Supported by US National Institutes of Health (NIH) Brain Tumor SPORE grant CA97257 (R.H., C.D.J.), the Pediatric Brain Tumor Foundation (R.H., N.G., C.D.J.), the Matthew Larson Foundation (R.H.), the Bear Necessities Pediatric Cancer Foundation (R.H.) and Rally Foundation (R.H.), American Cancer Society IRG-97-150-13 (R.H.), NIH CA157489 (Z.Z.), the Childhood Brain Tumor Foundation (C.P.), the Voices Against Brain Tumor Foundation (C.P.) and NIH CA164746 (C.P.). Publisher Copyright: {\textcopyright} 2014 Nature America, Inc. All rights reserved.",

year = "2014",

month = dec,

day = "1",

doi = "10.1038/nm.3716",

language = "English (US)",

volume = "20",

pages = "1394--1396",

journal = "Nature Medicine",

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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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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

N1 - Funding Information: Supported by US National Institutes of Health (NIH) Brain Tumor SPORE grant CA97257 (R.H., C.D.J.), the Pediatric Brain Tumor Foundation (R.H., N.G., C.D.J.), the Matthew Larson Foundation (R.H.), the Bear Necessities Pediatric Cancer Foundation (R.H.) and Rally Foundation (R.H.), American Cancer Society IRG-97-150-13 (R.H.), NIH CA157489 (Z.Z.), the Childhood Brain Tumor Foundation (C.P.), the Voices Against Brain Tumor Foundation (C.P.) and NIH CA164746 (C.P.). Publisher Copyright: © 2014 Nature America, Inc. All rights reserved.

PY - 2014/12/1

Y1 - 2014/12/1

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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