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.

The TP53 protein is known to affect the sensitivity of tumor cells to cell death by DNA damaging agents. We recently reported that human and mouse cells containing an African-specific coding region variant of p53, Pro47Ser (hereafter S47), are impaired in the transactivation of a small subset of p53 target genes including GLS2 and SCO2, and are markedly resistant to cisplatin. Further, mice containing this variant are markedly predisposed to cancer. Together these findings suggested that cancer-affected humans with the S47 variant might not be effectively treated with cisplatin. To more directly test this premise, we created transformed derivatives of mouse embryo fibroblasts (MEFs) containing wild type p53 (WT) and the S47 variant and analyzed them for chemosensitivity. We find that transformation with E1A and Ras actually reverses the chemosensitivity/transcriptional differences between WT p53 and S47. Specifically, E1A/Ras-transformed S47 cells show increased sensitivity to cisplatin and paclitaxel, and comparable transactivation of GLS2 and SCO2, compared to cells with WT p53. These data suggest that the functional differences between WT p53 and S47 in primary cells may not hold true for transformed cells. They also offer hope that cisplatin and paclitaxel may be effective chemotherapeutic drugs for S47 individuals with cancer.

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The purpose of this study was to examine the effectiveness of gastric feeding in prevention of upper gastrointestinal (GI) hemorrhage. A retrospective chart review of 50 consecutive burn intensive care unit patients with admission dates from January 1, 2005, to December 31, 2007, was conducted. Five of 50 patients (10%) developed GI hemorrhage. Three men of 36 developed a GI hemorrhage (8%) compared with 2 of 14 women (14%). Patients who developed hemorrhage had a higher abbreviated burn severity index score of 11 compared with the control group of 9 and having a higher mortality rate of 80% compared with controls of 27%. Those patients who developed abdominal compartment syndrome were more likely to develop GI hemorrhage (40% rate compared with 4% in patients who did not develop abdominal compartment syndrome). Of 13 patients who were not tolerating their tube feed at some point during treatment, 4 developed hemorrhage (31%), whereas only 1 patient who was tolerating his or her tube feed developed hemorrhage (3%). Three of 19 (16%) patients on proton pump inhibitor prophylaxis developed a GI hemorrhage compared with 2 of 31 (6%) of patients who were not undergoing prophylaxis. Because of the potential side effects of proton pump inhibitor prophylaxis, the authors believe that when tolerated, gastric feedings should be the standard prophylaxis to prevent upper gastrointestinal hemorrhage. Acid suppression therapy may only be necessary for patients who are not tolerating their tube feeds, have other abdominal pathologies, or with a previous history of peptic ulcer disease.

The telomeric repeat‐containing RNA, TERRA, associates with both telomeric DNA and telomeric proteins, often forming RNA:DNA hybrids (R‐loops). TERRA is most abundant in cancer cells utilizing the alternative lengthening of telomeres (ALT) pathway for telomere maintenance, suggesting that persistent TERRA R‐loops may contribute to activation of the ALT mechanism. Therefore, we sought to identify the enzyme(s) that regulate TERRA metabolism in mammalian cells. Here, we identify that the 5′–3′ exoribonuclease XRN2 regulates the stability of TERRA RNA. Moreover, while stabilization of TERRA alone was insufficient to drive ALT, depletion of XRN2 in ALT‐positive cells led to a significant increase in TERRA R‐loops and exacerbated ALT activity. Together, our findings highlight XRN2 as a key determinant of TERRA metabolism and telomere stability in cancer cells that rely on the ALT pathway.