Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

Kasper, Lawryn H.; Baker, Suzanne J.

doi:10.1111/nan.12591

Cited by 25 publications

(20 citation statements)

References 76 publications

(185 reference statements)

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“…For this reason, we will not go into detail on the state-of-the-art of this mutation in this work. The reader is referred to the following articles for further details [ 112 , 113 , 114 ].…”

Section: Genetic Alterations On Nbs Phggmentioning

confidence: 99%

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Haase

Nuñez

Gauss

et al. 2020

IJMS

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In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

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Section: Genetic Alterations On Nbs Phggmentioning

confidence: 99%

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Haase

Nuñez

Gauss

et al. 2020

IJMS

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“…Even initial studies showed disparate effects of different histone H3 genes and in different cell types, highlighting the nuanced consequences of chromatin dysregulation in oncogenesis. Below, we summarize the evolution of our current understanding of the downstream ramifications of oncohistone mutation in pediatric malignant glioma [ 49 , 50 , 51 ].…”

Section: Molecular Mechanisms Of Oncogenicitymentioning

confidence: 99%

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

Graham

Mellinghoff

2020

IJMS

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Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.

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“…Pediatric high-grade glioma is the leading cause of cancer death in children [1]. Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that arises in the brainstem, with an overall survival of only 11 months [2]. DIPG cannot be removed surgically, and there is no known effective treatment.…”

Section: Introductionmentioning

confidence: 99%

Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma

Camarillo

Huang

et al. 2020

J Exp Clin Cancer Res

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Background Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of the H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles. Methods We performed targeted mass spectrometry on H3.3K27M mutant and wild-type tissues (n = 12) and cell lines (n = 7). Results We found 29.2 and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in modification states were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors, relative to wild-type. Further, H3.3K36me2 was the most abundant co-occurring modification on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. JQ1 treatment resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. Conclusion Taken together, our findings provide insight into the effects of the H3K27M mutation on histone modification states and response to treatment, and suggest that H3K36me2 and H4K16ac may represent unique tumor epigenetic signatures for targeted DIPG therapy.

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Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

Cited by 25 publications

References 76 publications

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma

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