Somatic Mechanism Evolution of MDS and AML in Short Telomere Disorders

A study assessed the presence of somatic mechanisms in short telomere syndrome and their association with myelodysplastic syndromes and acute myeloid leukemia (MDS/AML). The results were published in The Journal of Clinical Investigation. To conduct this study, researchers used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among both controls and short telomere syndrome patients with and without MDS/AML. According to the results, while no controls carried somatic mutations in telomere maintenance genes, almost 30% of patients with germline telomere maintenance defects carried at least one mutation, and 13% had two or more mutations. Moreover, the researchers observed TERT promoter mutations in 19% of patients and POT1 and TERF2 interacting protein mutations in 13%. Overall, somatic reversion events in six telomere-related genes were found to be more prevalent in patients who were MDS/AML-free (P=0.02; relative risk, 4.4; 95% confidence interval 1.2-16.7), and no MDS/AML patient had more than one reversion mutation. “Our data identify diverse adaptive somatic mechanisms in the short telomere syndrome; they raise the possibility that their presence alleviates the telomere crisis that promotes transformation to MDS/AML,” the researchers concluded.