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Identification of a novel gene fusion in ALT positive osteosarcoma.


Maximus Peto’s Commentary

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).


Identification of a novel gene fusion in ALT positive osteosarcoma.
Oncotarget. 2018 Aug 28;9(67):32868-32880.
Mason-Osann E, Dai A, Floro J, Lock YJ, Reiss M, Gali H, Matschulat A, Labadorf A, Flynn RL
DOI: 10.18632/oncotarget.26029
PubMed publication date (edat): 9/15/2018

Abstract

The Alternative Lengthening of Telomeres (ALT) pathway stimulates telomere elongation and prevents cellular senescence in approximately 60% of osteosarcoma. While the precise mechanism underlying activation of the ALT pathway is unclear, mutations in the chromatin remodeling protein ATRX, histone chaperone DAXX, and the histone variant H3.3 correlate with ALT status. ATRX and DAXX facilitate deposition of the histone variant H3.3 within heterochromatic regions suggesting that loss of ATRX, DAXX, and/or H3.3 lead to defects in the stability of telomeric heterochromatin. Genetic mutations in ATRX, DAXX, and H3.3 have been detected in ALT positive cancers, however, a subset of ALT samples show loss of ATRX or DAXX protein expression or localization without evidence of genetic alterations suggesting additional uncharacterized defects in ATRX/DAXX/H3.3 function. Here, using Next Generation Sequencing we identified a novel gene fusion event between DAXX and the kinesin motor protein, KIFC3, leading to the translation of a chimeric DAXX-KIFC3 fusion protein. Moreover, we demonstrate that the fusion of KIFC3 to DAXX causes defects in DAXX function likely promoting ALT activity. These data highlight a potentially unrecognized mechanism of DAXX inactivation in ALT positive osteosarcoma and provide rationale for thorough and comprehensive analyses of ATRX/DAXX/H3.3 proteins in ALT positive cancers.
Comment in
* Genetic alterations associated with ALTered telomeres. [Oncotarget. 2018]

PMID: 30214690
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132345/

Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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