Oncotarget

Research Papers:

Identification of a novel gene fusion in ALT positive osteosarcoma

Emily Mason-Osann _, Anqi Dai, Jess Floro, Ying Jie Lock, Matthew Reiss, Himabindu Gali, Adeline Matschulat, Adam Labadorf and Rachel Litman Flynn

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Oncotarget. 2018; 9:32868-32880. https://doi.org/10.18632/oncotarget.26029

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Abstract

Emily Mason-Osann1, Anqi Dai2, Jess Floro1, Ying Jie Lock1, Matthew Reiss1, Himabindu Gali1, Adeline Matschulat3, Adam Labadorf2 and Rachel Litman Flynn1

1Departments of Pharmacology and Experimental Therapeutics, and Medicine Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA

2BU Bioinformatics Hub, Boston University, Boston, MA 02118, USA

3Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA

Correspondence to:

Rachel Litman Flynn, email: rlflynn@bu.edu

Keywords: telomeres; alternative lengthening of telomeres

Received: June 13, 2018     Accepted: August 15, 2018     Published: August 28, 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.


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