Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders

Abstract

Background. Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.Methods. We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and short telomere syndrome patients with and without MDS/AML and we tested the functional significance of these mutations.Results. While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least one (P<0.001) and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations which were present in 19%, we identified POT1 and TERF2IP mutations in 13%. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes, RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in six telomererelated genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2-16.7), and no MDS/AML patient had more than one reversion mutation. Conclusion.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.

Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita

“…Even though the patients with the compensatory mutations did not exhibit telomere lengthening effects, the mutations conferred the cells with a competitive advantage under the selective pressures of the short telomere environment. 48 This demonstrates the feasibility of our approach as long as the cells with TINF2 excision exhibit clonal expansion in vivo under selective pressure, which warrants further validation.…”

“…Recently, compensatory somatic mutations in TBD patients were shown to promote clonal expansion in the hematopoietic system. 48-50 These compensatory mutations include noncoding TERT promoter mutations and POT1 coding mutations as well as a cis somatic mutation on an RPA1 disease allele. Even though the patients with the compensatory mutations did not exhibit telomere lengthening effects, the mutations conferred the cells with a competitive advantage under the selective pressures of the short telomere environment.…”

Telomere-mediated lung disease

“…This estimate represents a nearly 200-fold increased risk relative to unselected populations ( 27 ). Recent evidence suggests that somatic reversion mutations, which functionally offset the inherited mutation (e.g., telomerase gain-of-function promoter mutations), may protect against the risk of myeloid malignancies ( 48 ). Short telomere IPF patients are also prone to syndromic patterns of noncirrhotic and cirrhotic liver disease ( 49 – 51 ).…”

“…There are multiple biological and clinical lines of evidence supporting that even when telomerase is restored, telomere length defects lag ( 105 ). For example, in one-third of IPF patients, somatic mutations that are “corrective” may be seen in the blood (e.g., TERT promoter gain-of-function mutations); however, even when nearly all cells acquire this advantageous mutation, there are no obvious telomere length or blood count improvements detected after a decade ( 48 , 110 ). These caveats present significant hurdles even if gene-directed delivery to alveolar stem cells were feasible.…”

Alveolar type 2 epithelial cell senescence and radiation-induced pulmonary fibrosis

“…The telomerase complex protects the telomeres from DNA damage and maintains the telomere intact. ( Schratz et al, 2021 ). The minimum length ensures the successful binding of telomere protection proteins to telomeres ( Li et al, 2017 ).…”