scholarly journals The H3K36me2 writer-reader dependency in H3K27M-DIPG

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.

scholarly journals The H3K36me2 writer-reader dependency in H3K27M-DIPG

2021 ◽  
Author(s):  
Jia-Ray Yu ◽  
Gary LeRoy ◽  
Devin Bready ◽  
Joshua D. Frenster ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Histone H3 ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Therapeutic Interventions ◽  
Functional Pathway ◽  
Proliferation In Vitro

AbstractThe lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, the placement of methylation at lysine 27 of histone H3 (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 in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic 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. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.

scholarly journals RTHP-36. REIRRADIATION FOR DIFFUSE INTRINSIC PONTINE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PATIENT OUTCOMES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi217-vi217
Author(s):  
Victor Lu ◽  
John Welby ◽  
Nadia Laack ◽  
Anita Mahajan ◽  
David Daniels
Keyword(s):  
Systematic Review ◽  
Patient Outcomes ◽  
Meta Analysis ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Limited Evidence ◽  
Dismal Prognosis ◽  
Clinical Consequences ◽  
Pediatric Brain

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG. METHODS Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies. RESULTS A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8–14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78–95%) and 69% (95% CI, 52–84%) respectively. The incidence of acute serious toxicity was 0% (95% CI, 0–4%). Pooled overall survivals from initial diagnosis, and time of reRT, were 18.0 months (95% CI, 14.2–21.7) and 6.2 months (95% CI, 5.5–7.0) respectively. CONCLUSIONS Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely a sub-cohort of all DIPG diagnoses will be most amenable to improved prognosis with reRT, and greater investigation is required to identify their characteristics.

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