Cancer and myeloid clonal evolution in the short telomere syndromes

•Myelodysplastic syndrome and acute myeloid leukemia are the most common short telomere malignancies.•Clonal hematopoiesis is common in adult short telomere syndrome patients.•Longer telomeres may allow clonal evolution to MDS, in contrast to aplastic anemia. 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.