Specific death of ALT cells through TSPYL5 depletion

Claude, Eloïse; Episkopou, Harikleia; Decottignies, Anabelle

doi:10.1080/23723556.2019.1651603

Cited by 1 publication

(3 citation statements)

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“…Paediatric cancers, because of i) the higher prevalence of ALT and ii) the urgent need to develop targeted therapies, may notably benefit from such tools. Paediatric cancers indeed dramatically suffer from the lack of new less toxic therapies and the ALT mechanism, being absent from normal cells, offers interesting perspectives in this regard [8]. To re-evaluate the currently available tools for ALT screening, and to develop new assays, on either FFPE or frozen tumor sections, we first set up the LB857/ ALT + -derived mouse xenograft model.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…This results mainly from the fact that ALT relies on homologous recombination events between telomeric DNA sequences and seems to operate mostly through a bifurcated break-induced replication pathway [ 6 ] that, in its enzymatic requirements, does not differ from the DNA repair pathways that are used by the cells in response to DNA damage. If targeting homologous recombination does not offer specific therapeutic perspectives for ALT + cancer treatment, the discovery that disrupting the interaction between TSPYL5 and USP7 seems to specifically induce ALT + cell death offers alternative perspectives [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Detection of alternative lengthening of telomeres mechanism on tumor sections

et al. 2021

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The vast majority of adult cancer cells achieve cellular immortality by activating a telomere maintenance mechanism (TMM). While this is mostly achieved by the de-silencing of hTERT telomerase gene expression, an alternative homologous recombination-based and telomerase-independent mechanism, known as ALT (Alternative Lengthening of Telomeres), is frequently activated in a subset of tumors, including paediatric cancers. Being absent from normal cells, the ALT mechanism offers interesting perspectives for new targeted cancer therapies. To date, however, the development of better translationally applicable tools for ALT detection in tumor sections is still needed. Here, using a newly derived ALT-positive cancer cell mouse xenograft model, we extensively examined how the previously known ALT markers could be used as reliable tools for ALT diagnosis in tumor sections. We found that, together with the detection of ultra-bright telomeric signals (UBS), an ALT hallmark, native telomeric FISH, that detects single-stranded C-rich telomeric DNA, provides a very sensitive and robust tool for ALT diagnosis in tissues. We applied these assays to paediatric tumor samples and readily identified three ALT-positive tumors for which the TMM was confirmed by the gold-standard C-circle amplification assay. Although the latter offers a robust assay for ALT detection in the context of research laboratories, it is more difficult to set up in histopathological laboratories and could therefore be conveniently replaced by the combination of UBS detection and native telomeric FISH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%