Cancer cells activate telomere maintenance mechanisms (TMMs) to overcome senescence and thus are targets for TMM-specific therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is frequently utilized as a TMM in human sarcoma subtypes. Histiocytic sarcoma (HS) is a rare but aggressive tumor of hematopoietic origin with unknown ALT incidence in humans. ALT has been identified in canine HS, a tumor type comparable to human HS that occurs with high rates in certain canine breeds such as Bernese mountain dogs (BMDs). This retrospective study characterized the frequency of ALT in BMD and non-BMD patients diagnosed with HS as surrogates for humans. Formalin-fixed paraffin-embedded tumor samples from 63 dogs at two centers, including 47 BMDs, were evaluated for their ALT activity and relative telomere content (TC) using a radiolabel C-circle assay (CCA). Known ALT-positive samples served as controls. CCA-positive cases were validated via FISH. Two BMD samples showed ALT activity of 1–14% compared to controls. All other samples were ALT-negative. The TC did not correlate with the CCA results. ALT positivity was validated by the appearance of ultrabright telomere foci. Low ALT activity was present in 4% of BMDs with HS and therefore does not appear to be a common target for therapeutic approaches but can have diagnostic value.
癌细胞通过激活端粒维持机制（TMM）来克服衰老，因此成为TMM特异性治疗的靶点。在人类肉瘤亚型中，不依赖端粒酶的端粒替代延长（ALT）常被用作一种TMM。组织细胞肉瘤（HS）是一种罕见但具有侵袭性的造血系统肿瘤，其在人类中的ALT发生率尚不明确。而在犬类HS中已发现ALT的存在，这种肿瘤类型与人类HS相似，在某些犬种（如伯恩山犬）中发病率较高。本回顾性研究以伯恩山犬与非伯恩山犬确诊HS的病例作为人类替代模型，分析了ALT的发生频率。研究采用放射性标记C环检测法（CCA）对来自两个中心的63只犬（包括47只伯恩山犬）的石蜡包埋肿瘤样本进行ALT活性和相对端粒含量（TC）评估，并以已知ALT阳性样本作为对照。CCA阳性病例通过荧光原位杂交（FISH）进行验证。结果显示，与对照组相比，两例伯恩山犬样本显示出1-14%的ALT活性，其余样本均为ALT阴性。TC与CCA结果无相关性。ALT阳性通过超亮端粒灶的出现得到确认。在患有HS的伯恩山犬中，仅4%存在低水平ALT活性，这表明ALT并非常见的治疗靶点，但可能具有诊断价值。
Alternative Lengthening of Telomeres Is Rare in Canine Histiocytic Sarcoma
肿瘤(癌症)患者之家