Untangling the role of mutant histone H3 in diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGGs). The expression and sub-cellular location of H19 lncRNA were validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs. normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.

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Characterization of the Blood–Brain Barrier Integrity and the Brain Transport of SN-38 in an Orthotopic Xenograft Rat Model of Diffuse Intrinsic Pontine Glioma

Pharmaceutics ◽

10.3390/pharmaceutics12050399 ◽

2020 ◽

Vol 12 (5) ◽

pp. 399 ◽

Cited By ~ 2

Author(s):

Catarina Chaves ◽

Xavier Declèves ◽

Meryam Taghi ◽

Marie-Claude Menet ◽

Joelle Lacombe ◽

...

Keyword(s):

Blood Brain Barrier ◽

Diffuse Intrinsic Pontine Glioma ◽

Brain Barrier ◽

Brain Delivery ◽

Pontine Glioma ◽

Anticancer Drug Delivery ◽

Blood Brain ◽

The Brain

The blood–brain barrier (BBB) hinders the brain delivery of many anticancer drugs. In pediatric patients, diffuse intrinsic pontine glioma (DIPG) represents the main cause of brain cancer mortality lacking effective drug therapy. Using sham and DIPG-bearing rats, we analyzed (1) the brain distribution of 3-kDa-Texas red-dextran (TRD) or [14C]-sucrose as measures of BBB integrity, and (2) the role of major ATP-binding cassette (ABC) transporters at the BBB on the efflux of the irinotecan metabolite [3H]-SN-38. The unaffected [14C]-sucrose or TRD distribution in the cerebrum, cerebellum, and brainstem regions in DIPG-bearing animals suggests an intact BBB. Targeted proteomics retrieved no change in P-glycoprotein (P-gp), BCRP, MRP1, and MRP4 levels in the analyzed regions of DIPG rats. In vitro, DIPG cells express BCRP but not P-gp, MRP1, or MRP4. Dual inhibition of P-gp/Bcrp, or Mrp showed a significant increase on SN-38 BBB transport: Cerebrum (8.3-fold and 3-fold, respectively), cerebellum (4.2-fold and 2.8-fold), and brainstem (2.6-fold and 2.2-fold). Elacridar increased [3H]-SN-38 brain delivery beyond a P-gp/Bcrp inhibitor effect alone, emphasizing the role of another unidentified transporter in BBB efflux of SN-38. These results confirm a well-preserved BBB in DIPG-bearing rats, along with functional ABC-transporter expression. The development of chemotherapeutic strategies to circumvent ABC-mediated BBB efflux are needed to improve anticancer drug delivery against DIPG.

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TMIC-25. TUMOR MIGRATION AND ROLE OF MICROENVIRONMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/nox168.1014 ◽

2017 ◽

Vol 19 (suppl_6) ◽

pp. vi248-vi248 ◽

Cited By ~ 1

Author(s):

Madhuri Kambhampati ◽

Eshini Panditharatna ◽

Sridevi Yadavilli ◽

Cheng-Ying Ho ◽

Lindsay Kilburn ◽

...

Keyword(s):

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma

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The Role of Early Post Radiation MRI Scans in Children with Diffuse Intrinsic Pontine Glioma (DIPG)

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2010.07.1386 ◽

2010 ◽

Vol 78 (3) ◽

pp. S594-S595

Author(s):

A. Kaushal ◽

C. Ko ◽

D. Hammoud ◽

E. Steffan-Smith ◽

D. Citrin ◽

...

Keyword(s):

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma ◽

Mri Scans ◽

Post Radiation

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Role of Early Postradiation Magnetic Resonance Imaging Scans in Children With Diffuse Intrinsic Pontine Glioma

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2011.09.046 ◽

2012 ◽

Vol 83 (4) ◽

pp. 1252-1256 ◽

Cited By ~ 2

Author(s):

Christine Ko ◽

Aradhana Kaushal ◽

Dima A. Hammoud ◽

Emilie A. Steffen-Smith ◽

Robyn Bent ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Diffuse Intrinsic Pontine Glioma ◽

Resonance Imaging ◽

Pontine Glioma

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The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma

Oncotarget ◽

10.18632/oncotarget.3716 ◽

2015 ◽

Vol 6 (14) ◽

pp. 12141-12155 ◽

Cited By ~ 19

Author(s):

Sridevi Yadavilli ◽

Joseph Scafidi ◽

Oren J. Becher ◽

Amanda M. Saratsis ◽

Rebecca L. Hiner ◽

...

Keyword(s):

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma

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The long non-coding RNA H19 drives the proliferation of diffuse intrinsic pontine glioma with H3K27 mutation

10.1101/2021.07.19.452516 ◽

2021 ◽

Author(s):

Francesco Crea

Keyword(s):

Large Family ◽

Diffuse Intrinsic Pontine Glioma ◽

Locked Nucleic Acid ◽

Normal Brain ◽

Pontine Glioma ◽

Incurable Cancer ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Long Non Coding Rna

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying molecular drivers of DIPG progression is of utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not been yet elucidated in DIPG. Here, we study the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGG). Expression and sub-cellular location of H19 lncRNA was validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in up-regulation of oncogenic let-7 target (e.g SULF2, OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate to treat this incurable cancer.

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The H3K36me2 writer-reader dependency in H3K27M-DIPG

Science Advances ◽

10.1126/sciadv.abg7444 ◽

2021 ◽

Vol 7 (29) ◽

pp. eabg7444

Author(s):

Jia-Ray Yu ◽

Gary LeRoy ◽

Devin Bready ◽

Joshua D. Frenster ◽

Ricardo Saldaña-Meyer ◽

...

Keyword(s):

Catalytic Activity ◽

Cellular Proliferation ◽

Pediatric Brain Tumor ◽

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma ◽

Chemically Modified ◽

Functional Pathway ◽

Pediatric Brain ◽

Global Inhibition

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.

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Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies

Cancers ◽

10.3390/cancers13040607 ◽

2021 ◽

Vol 13 (4) ◽

pp. 607

Author(s):

Jean Yin Tan ◽

Ipalawattage Vindya Stephnie Wijesinghe ◽

Muhamad Noor Alfarizal Kamarudin ◽

Ishwar Parhar

Keyword(s):

Histone H3 ◽

Diffuse Intrinsic Pontine Glioma ◽

Braf V600e Mutation ◽

Diagnostic Methods ◽

Prognostic Biomarkers ◽

Braf V600e ◽

Low Grade ◽

High Grade ◽

Pontine Glioma ◽

Liquid Biopsies

Paediatric gliomas categorised as low- or high-grade vary markedly from their adult counterparts, and denoted as the second most prevalent childhood cancers after leukaemia. As compared to adult gliomas, the studies of diagnostic and prognostic biomarkers, as well as the development of therapy in paediatric gliomas, are still in their infancy. A body of evidence demonstrates that B-Raf Proto-Oncogene or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and histone H3 mutations are valuable biomarkers for paediatric low-grade gliomas (pLGGs) and high-grade gliomas (pHGGs). Various diagnostic methods involving fluorescence in situ hybridisation, whole-genomic sequencing, PCR, next-generation sequencing and NanoString are currently used for detecting BRAF and histone H3 mutations. Additionally, liquid biopsies are gaining popularity as an alternative to tumour materials in detecting these biomarkers, but still, they cannot fully replace solid biopsies due to several limitations. Although histone H3 mutations are reliable prognosis biomarkers in pHGGs, children with these mutations have a dismal prognosis. Conversely, the role of BRAF alterations as prognostic biomarkers in pLGGs is still in doubt due to contradictory findings. The BRAF V600E mutation is seen in the majority of pLGGs (as seen in pleomorphic xanthoastrocytoma and gangliomas). By contrast, the H3K27M mutation is found in the majority of paediatric diffuse intrinsic pontine glioma and other midline gliomas in pHGGs. pLGG patients with a BRAF V600E mutation often have a lower progression-free survival rate in comparison to wild-type pLGGs when treated with conventional therapies. BRAF inhibitors (Dabrafenib and Vemurafenib), however, show higher overall survival and tumour response in BRAF V600E mutated pLGGs than conventional therapies in some studies. To date, targeted therapy and precision medicine are promising avenues for paediatric gliomas with BRAF V600E and diffuse intrinsic pontine glioma with the H3K27M mutations. Given these shortcomings in the current treatments of paediatric gliomas, there is a dire need for novel therapies that yield a better therapeutic response. The present review discusses the diagnostic tools and the perspective of liquid biopsies in the detection of BRAF V600E and H3K27M mutations. An in-depth understanding of these biomarkers and the therapeutics associated with the respective challenges will bridge the gap between paediatric glioma patients and the development of effective therapies.

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