The short telomere syndromes are considered the most common premature aging disorders. Although studies in genetically modified cells and animal models have suggested telomere dysfunction may promote genome instability, only a minority of humans with inherited loss-of-function mutations in telomerase and related genes develop cancer. Solid tumors are overall rare, and the vast majority of cancers are bone marrow-derived with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprising three-quarter of cases. In contrast to young short telomere syndrome patients who develop aplastic anemia, MDS and AML are usually diagnosed in adults who have milder short telomere defects. Here, we dissect the mechanisms by which these two bone marrow failure states, aplastic anemia and MDS-AML, evolve in the setting of varying degrees of telomere shortening. We discuss the implications of these observations for patient care as well as for understanding the genetics and biology of age-related myeloid clonal evolution.

中文翻译：

---

短端粒综合征中的癌症和骨髓克隆进化。

短端粒综合征被认为是最常见的早衰症。尽管对转基因细胞和动物模型的研究表明端粒功能障碍可能会促进基因组不稳定，但只有少数在端粒酶和相关基因中遗传了功能缺失突变的人类会患上癌症。实体瘤总体上很少见，并且绝大多数癌症是骨髓源性骨髓增生异常综合症（MDS）和急性髓细胞性白血病（AML），占四分之三。与发展性再生障碍性贫血的年轻短端粒综合征患者相比，MDS和AML通常在患有较轻端粒端粒缺陷的成人中被诊断出。在这里，我们剖析了这两种骨髓衰竭状态（再生障碍性贫血和MDS-AML）的机制，在不同程度的端粒缩短的环境中进化。我们讨论了这些观察结果对患者护理以及对与年龄相关的骨髓克隆进化的遗传学和生物学的理解的意义。