LAUSR

To maintain genome stability, proliferating cells must add telomere sequence to counteract the chromosome end replication problem. In normal cells, telomeres are lengthened through the action of the enzyme telomerase. In about 10-15% of tumors, however, telomeres are lengthened through a telomerase-independent mechanism known as Alternative Lengthening of Telomeres or ALT. Many tumors that use ALT have poor prognoses, so ALT represents an appealing therapeutic target. It has been previously observed that ALT tumors frequently carry mutations in ATRX, which partners with the protein DAXX in a chromatin remodeling complex that deposits histone variant H3.3. How these mutations facilitate the ALT pathway is not well understood. Previous work in our lab identified an ALT-positive osteosarcoma cell line, G292, in which ATRX is wild-type but DAXX has undergone a fusion event with the non-canonical kinesin KIFC3. The DAXX-KIFC3 fusion leads to a loss of DAXX function, and inducible restoration of wild-type DAXX reversibly abrogates ALT in this cell line. We observe that expression of wild-type DAXX results in localization of ATRX to PML bodies, increased occupancy of ATRX at telomeric chromatin, and higher levels of histone H3.3 at telomeres. We conclude that full-length DAXX is required for the functional localization of ATRX to telomeres. Leveraging this our inducible system, we continue to probe the role of the ATRX/DAXX complex in suppressing ALT. Citation Format: Sarah Faith Clatterbuck Soper, Kathryn E. Yost, Robert L. Walker, Marbin A. Pineda, Yuelin J. Zhu, Joshua J. Waterfall, Paul S. Meltzer. DAXX localizes ATRX to suppress alternative lengthening of telomeres in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1466.