Dissecting telomere maintenance mechanisms in pediatric glioblastoma

Deeg, Katharina I.; Chung, Inn; Poos, Alexandra M; Braun, Delia M.; Korshunov, Andrey; Oswald, Marcus; Kepper, Nick; Bender, Sebastian; Castel, David; Lichter, Peter; Grill, Jacques; Pfister, Stefan M.; König, Rainer; Jones, David; Rippe, Karsten

doi:10.1101/129106

Cited by 5 publications

(9 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Each of the six tumors analyzed showed the same hypomethylated promoter status. The association between promoter hypomethylation and low expression has also been reported for human TERT in brain cancer (Deeg et al, 2017). This relation suggests that promoter hypomethylation is a general feature of negative regulation of tert expression, perhaps due to the location of the gene in a subtelomeric region (CHR5:1253147-1295069, GRCh38/hg38), both in human and in zebrafish (Figure 2C, inset).…”

Section: Telomerase Is Not Involved In Tmm In Zebrafish Brain Tumorssupporting

confidence: 65%

“…We found that zebrafish tumors rely on ALT as TMM, similarly to many pediatric GBMs. With the increasing number of reports documenting a prevalence of ALT in some pediatric cancers (Heaphy et al, 2011;Dorris et al, 2014;Deeg et al, 2017) the role of the embryonic origin of these tumors in the ability to activate telomerase or ALT during cancer progression is becoming evident.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of tert Prevents ALT in Zebrafish Brain Tumors

Idilli

Cusanelli

Pagani

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Alternative lengthening of telomeres (ALT) is found in a subset of malignant brain tumors with poor outcomes. Here, we describe a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert, linked to a widespread hypomethylation of the tert promoter and increase in Terra expression precedes ALT development. Surprisingly, expression of tert during juvenile brain tumor development led to reduced proliferation of tumor cells and prolonged survival. Most importantly, expression of tert reverted all ALT features and normalizes TERRA expression, promoted heterochromatin formation at telomeres, and attenuated telomeric DNA damage. These data suggest that the activity of telomerase goes beyond telomere maintenance and has profound consequences on genome stability.

show abstract

Section: Telomerase Is Not Involved In Tmm In Zebrafish Brain Tumorssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Expression of tert Prevents ALT in Zebrafish Brain Tumors

Idilli

Cusanelli

Pagani

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Each of the six tumours analyzed showed the same hypomethylated promoter status. The association between promoter hypomethylation and low expression has been reported also for human TERT in brain cancer 33 . This relation suggests that promoter hypomethylation is a general feature of negative regulation of tert expression, perhaps due to the location of the gene in a subtelomeric region (CHR5:1253147-1295069, GRCh38/hg38), both in human and in zebrafish (Figure 2c, inset).…”

Section: Telomerase Is Not Involved In Tmm In Zebrafish Brain Tumoursmentioning

confidence: 61%

“…These experiments confirmed an increase in TERRA levels in tumors as compared to control brains (Figure 4e), which is consistent with the RNA-FISH results. Finally, TERRA expression levels were quantified by performing quantitative reverse transcription PCR using total RNA obtained from control and brain tumours 33 and compared to TERRA levels in HeLa and U2OS cells. By these analyses, we found that TERRA levels in tumours were almost 3-fold higher than in control brains (Figure 4f, left panel).…”

Section: Co-fish 36 Experimentsmentioning

confidence: 99%

Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors

Idilli

Cusanelli

Pagani

et al. 2019

Preprint

View full text Add to dashboard Cite

The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear.Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT.We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks at chromosome ends. Surprisingly, expression of telomerase reverts ALT features. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed increase of telomeric heterochromatin and maintenance of telomere length compared to ALT tumors, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of telomeric DNA replication and chromatin status in brain cancers. of cancers use alternative lengthening of telomeres (ALT), a mechanism based on homologous recombination between telomeres 3 . The molecular details of ALT activation remain to be defined 4 . ALT is found mostly in tumors with a mesenchymal origin (sarcoma) and in a subset of malignant paediatric brain tumors 5 , including High Grade Glioma (HGG, 51%), Diffuse Intrinsic Pontine Glioma (DIPG) (18%), Choroid Plexus Carcinoma (CPC) (22.6%), and Primitive Neuroectodermal Tumors (PNET) (11.6%) 6,7 . HGGs represent approximately 3-5% of childhood brain tumors and include a heterogeneous group of rare but aggressive tumors 8 , which remains largely incurable, with the most aggressive forms being lethal within months. In contrast with adult glioma, mutations within the promoter region of the telomerase catalytic subunit, TERT, occur at a lower rate in paediatric tumors (3-11% compared to 55-83% in adult tumors) 9 . Indeed, paediatric gliomas show distinctive genetic mutations, which suggest that the mechanisms of tumor development and progression are different from those identified in adult brain tumors, where ALT develops in approximately 15% of cases, and associates with IDH1 mutations and better prognosis 10 .Exon sequencing of paediatric HGGs identified recurrent somatic mutations (K27M, G34R/V) in histone H3 11,12 , and inactivating mutations in the Death-domain associated protein/Alpha thalassemia-mental retardation (DAXX/ATRX) genes, leading to DNA hypomethylation 13,14,15 .These findings suggest that telomeric chromatin plays an important role in ALT. Altered histone modifications in subtelomeric regions in association with ATRX loss result in deregulated telomere length and chromosomal instability, features that are often associated with ALT 4 . Notably, ALT activation can be inferred by a number of other features, including the presence of heterogeneous telomeres, w...

show abstract

“…Furthermore, little evidence was found for ALT in these tumors, with only one sample being positive in a study comprising 60 tumor specimens [180]. In contrast, about half of all pediatric high grade gliomas (PHGGs) is positive for ALT, and a smaller subgroup of about 23% has activated telomerase, with TERT promoter mutations and chromothripsis being quite uncommon [104,180,199,243]. Adult high-grade gliomas show the reverse pattern [243].…”

Section: Brain Tumorsmentioning

confidence: 99%

Telomere Maintenance in Pediatric Cancer

Ackermann

Fischer

2019

IJMS

View full text Add to dashboard Cite

Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases and cancer. Substantial progress has been made in recent decades in understanding the complex molecular relationships in this research field. However, the majority of telomere studies have been conducted in adults. The data on telomere dynamics in pediatric cancers is limited, and interpretation can be challenging, especially in cases where results are contrasting to those in adult entities. This review describes recent advances in the molecular characterization of structure and function of telomeres, regulation of telomerase activity in cancer pathogenesis in general, and highlights the key advances that have expanded our views on telomere biology in pediatric cancer, with special emphasis on the central role of telomere maintenance in neuroblastoma. Furthermore, open questions in the field of telomere maintenance research are discussed in the context of recently published literature.

show abstract

Dissecting telomere maintenance mechanisms in pediatric glioblastoma

Cited by 5 publications

References 76 publications

Expression of tert Prevents ALT in Zebrafish Brain Tumors

Expression of tert Prevents ALT in Zebrafish Brain Tumors

Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors

Telomere Maintenance in Pediatric Cancer

Contact Info

Product

Resources

About