Loss of <scp>H3K27</scp> trimethylation in a distinct group of de‐differentiated chordoma of the skull base

Makise, Naohiro; Shimoi, Tatsunori; Sunami, Kuniko; Aoyagi, Yasuko; Kobayashi, Hiroshi; Tanaka, Shota; Kawai, Akira; Yonemori, Kan; Ushiku, Tetsuo; Yoshida, Akihiko

doi:10.1111/his.14823

Cited by 6 publications

(2 citation statements)

References 52 publications

(132 reference statements)

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“…Multiple studies have shown the importance of brachyury in the pathogenesis of chordoma [ 14 , 15 , 41 ]. However, some poorly differentiated and dedifferentiated chordoma display the loss of brachyury [ 42 , 43 ], SMARCB1/INI1 [ 44 , 45 ] or H3K27 trimethylation [ 46 ], TP53 mutation [ 42 ], and NF-ĸB activation [ 43 ]. These data suggest that the most common subtype of chordoma may potentially benefit from our VLP-delivered Cas9/gRNA RNP-based gene editing therapeutic approach, whereas poorly differentiated and dedifferentiated chordoma would not benefit from this approach.…”

Section: Discussionmentioning

confidence: 99%

Virus-like particle-based delivery of Cas9/guide RNA ribonucleoprotein efficiently edits the brachyury gene and inhibits chordoma growth in vivo

Lü

Deng

et al. 2023

Discov Onc

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Purpose Chordoma is a rare and aggressive bone cancer driven by the developmental transcription factor brachyury. Efforts to target brachyury are hampered by the absence of ligand-accessible small-molecule binding pockets. Genome editing with CRISPR systems provides an unprecedented opportunity to modulate undruggable transcription factor targets. However, delivery of CRISPR remains a bottleneck for in vivo therapy development. The aim was to investigate the in vivo therapeutic efficiency of Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) delivery through a novel virus-like particle (VLP) by fusing an aptamer-binding protein to the lentiviral nucleocapsid protein. Methods The p24 based ELISA and transmission electron microscopy were used to determine the characterization of engineered VLP-packaged Cas9/gRNA RNP. The deletion efficiency of brachyury gene in chordoma cells and tissues was measured by genome cleavage detection assay. RT-PCR, Western blot, immunofluorescence staining, and IHC were employed to test the function of brachyury deletion. Cell growth and tumor volume were measured to evaluate the therapeutic efficiency of brachyury deletion by VLP-packaged Cas9/gRNA RNP. Results Our “all-in-one” VLP-based Cas9/gRNA RNP system allows for transient expression of Cas9 in chordoma cells, but maintains efficient editing capacity leading to approximately 85% knockdown of brachyury with subsequent inhibition of chordoma cell proliferation and tumor progression. In addition, this VLP-packaged brachyury-targeting Cas9 RNP avoids systemic toxicities in vivo. Conclusion Our preclinical studies demonstrate the potential of VLP-based Cas9/gRNA RNP gene therapy for the treatment of brachyury-dependent chordoma.

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Section: Discussionmentioning

confidence: 99%

Virus-like particle-based delivery of Cas9/guide RNA ribonucleoprotein efficiently edits the brachyury gene and inhibits chordoma growth in vivo

Lü

Deng

et al. 2023

Discov Onc

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“…Other studies have found that other methylation patterns in MPNST, such as dimethyl loss at H3K27, may be more specific when using immunohistochemistry [15]. Since its role in MPNST, H3K27me3 has been implicated in a number of different tumors for diagnostic and prognostic purpose, often associated with a poor prognosis or aggressive behavior, including rhabdomyosarcoma [16], chordoma [17], CNS tumors [18], amongst others.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Study of Histone Protein 3 Modification in Pediatric Osteosarcoma Identifies Reduced H3K27me3 as a Marker of Poor Treatment Response

Kondratowski,

Cohen,

Deyell

et al. 2023

Preprint

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The most common pediatric primary malignant bone tumor, osteosarcoma, is often described as genetically non-recurrent and heterogeneous. Neoadjuvant chemotherapy is typically followed by resection and assessment of treatment response, which helps inform prognosis. Identifying biomarkers that may impact chemotherapy response and survival could aid in upfront risk stratification and identify patients in highest need of innovative therapies for future clinical trials. Relative to conventional genetics, little is known about osteosarcoma epigenetics. We aimed to characterize the methylation and phosphorylation status in osteosarcoma using histone markers found in primary diagnostic biopsies and their paired metastases. We constructed two tissue microarray sets from 58 primary diagnostic samples and 54 temporally-separated but related metastatic or recurrent samples, with tissue blocks available from 2002-2022. Clinical charts were reviewed for post-therapy necrosis response, presence of metastatic disease or recurrence, and overall survival. We evaluated 6 histone H3 residues using immunohistochemistry, including H3K4me3, H3K9me3, H3K27me2, H3K27me3, H3S10T11phos, and H3S28phos. Tumors were scored with low (<25%) or high (≥25%) nuclear staining of tumor cells. Diagnostic biopsies with low H3K27me3 nuclear staining were associated with poor treatment response (≤90% necrosis) at the time of definitive excision (P<0.05). We observed loss of H3S10T11phos expression in metastatic and recurrent resections specimens compared to the primary tumor (P<0.05). Expression patterns for the remaining histone markers did not show significant associations with disease parameters or survival. Although larger cohort studies are needed, these results support the expanded evaluation of histone markers, particularly H3K27me3 and H3S10T11phos, in osteosarcoma biology and risk stratification.

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H3K27me3 deficiency in dedifferentiated carcinoma and carcinosarcoma of the endometrium

Kihara,

Amano,

Fukushima

et al. 2023

Virchows Arch

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Loss of H3K27 trimethylation in a distinct group of de‐differentiated chordoma of the skull base

Abstract: De-differentiated chordoma with H3K27me3 loss 421

Cited by 6 publications

References 52 publications

Virus-like particle-based delivery of Cas9/guide RNA ribonucleoprotein efficiently edits the brachyury gene and inhibits chordoma growth in vivo

Virus-like particle-based delivery of Cas9/guide RNA ribonucleoprotein efficiently edits the brachyury gene and inhibits chordoma growth in vivo

Immunohistochemical Study of Histone Protein 3 Modification in Pediatric Osteosarcoma Identifies Reduced H3K27me3 as a Marker of Poor Treatment Response

H3K27me3 deficiency in dedifferentiated carcinoma and carcinosarcoma of the endometrium

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