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Rapid and reversible suppression of ALT by DAXX in osteosarcoma cells.

From the title, this paper looked especially interesting. Reading the abstract, it seems like ALT activity was activated by a problem with DAXX, and ALT was suppressed by re-introducing a wild-type DAXX. So this intervention may only be addressing a very specific problem (with DAXX), and not capable of eliminating ALT in all cases. This may still have important relevance for understanding and addressing ALT tumors, but it may instead only be relevant for tumors that develop ALT capability from dysfunctions in DAXX.
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Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.

This seems like a clever, if unusual, method of targeting ALT+ cancer cells. This group found that ATRX deficiency "creates a vulnerability" that they exploited by infecting these cells with a mutant herpes simplex virus-1 (HSV-1), which could infect these ALT+ cells "ten- to one thousand-fold more effective[ly] than wild-type ATRX-expressing cells." Moreover, this mutant HSV-1 "selectively killed ATRX-deficient cells". I wonder if this might be a technique to target ALT+ cancer cells with a cell-killing virus, while leaving normal cells relatively unaffected.
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RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening.

I reported recently on another group's findings about the relevance of RAD52 to ALT activity (see PMID 30673617). The current study appears to suggest that (1) RAD52 is involved in ALT activity, perhaps by its loss, and (2) SLX4 may be necessary for ALT, because its impairment at the same time as RAD52 deficiency "resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity." But perhaps I'm misunderstanding this abstract.
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Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways.

From my brief time working on the SRF OncoSENS project about ALT in 2012, I recall discussions about whether ALT activity may be induced by a gain-of-function change, or a loss-of-function change. The authors of this paper suggest that C-circle activity appears to be regulated by more than one pathway. At least in this model, ALT activity required RAD52 activity, but this pathway is not necessary for C-circle formation. Knocking out RAD52 in ALT cells could cause a gradual shortening of telomeres, but C-circles can still be formed. ALT cell DNA synthesis could also increase as telomeres shortened, but it's not clear to me whether this meant that telomeres could still be maintained without RAD52.
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Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.

Here we are with yet another report of loss of ATRX/DAXX implicated in ALT activity, this time in uterine leiomyomas. I scanned the full-text to see if I could find anything particularly interesting to report or clarify, and here is something that seemed interesting: "The great majority of conventional ULs harbor mutations in MED12 or overexpress HMGA2.3 Tumors with either one of these driver mutations display relatively few other mutations. Here, 53 of 64 conventional tumors (83%) displayed either a MED12 mutation or HMGA2 overexpression...All tumors with ATRX/DAXX loss or ALT were wild‐type for MED12 and HMGA2 (Table 1)." It seems interesting that **all** tumors with loss of ATRX/DAXX loss or ALT-positivity did not have mutations in, or overexpression of, a protein that 83% of tumors had. I wonder why these are so mutually exclusive.
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Identification of a novel gene fusion in ALT positive osteosarcoma.

This group reports on an apparently novel gene fusion between DAXX and KIFC3 in an ALT-positive osteosarcoma cell line. They found that this fusion caused DAXX dysfunction that was "likely promoting ALT activity". I leave it to other researchers on this distribution list to study the details and determine whether the DAXX dysfunction from this gene fusion might be a primary cause of ALT activity in ALT-positive cancers more broadly. If it is, perhaps there is some way to target cells possessing this fusion (to edit the fusion in their DNA or destroy them).
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