Recent advances in understanding telomere diseases

Abstract

Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to interstitial lung disease and liver cirrhosis, from childhood (dyskeratosis congenita) to old age (pulmonary fibrosis). The molecular mechanisms underlying these clinically distinct disorders are pathologically excessive telomere erosion, limiting cell proliferation and differentiation, tissue regeneration, and increasing genomic instability. Recent findings also indicate that telomere shortening imbalances stem cell fate and is associated with an abnormal inflammatory response and the senescent-associated secretory phenotype. Bone marrow failure is the most common phenotype in patients with telomere diseases. Pulmonary fibrosis is a typical phenotype in older patients, and disease progression appears faster than in pulmonary fibrosis not associated with telomeropathies. Liver cirrhosis may present in isolation or in combination with other phenotypes. Diagnosis is based on clinical suspicion and may be confirmed by telomere length measurement and genetic testing. Next-generation sequencing (NGS) techniques have improved genetic testing; today, at least 16 genes have been implicated in telomeropathies. NGS also allows tracking of clonal hematopoiesis and malignant transformation. Patients with telomere diseases are at high risk of developing cancers, including myeloid neoplasms and head and neck cancer. However, treatment options are still limited. Transplant modalities (bone marrow, lung, and liver) may be definitive to the respective organ involvement but limited by donor availability, comorbidities, and impact on other affected organs. In clinical trials, androgens elongate telomeres of peripheral blood leukocytes and improve hematopoiesis. Further understanding of how telomere erosion impairs organ function and how somatic mutations evolve in the hematopoietic tissue may help develop new strategies to treat and prevent telomere diseases.

Keywords: aplastic anemia; dyskeratosis congenita; liver cirrhosis; myeloid neoplasm; pulmonary fibrosis; telomerase; telomere.

Figure 1.. Telomeres and telomerase.

(A) The telomerase complex is composed of the reverse transcriptase telomerase, the RNA template TERC, and associated proteins. It adds hexameric repeats to the 3′ end of the leading DNA telomeric strand. (B) Percentile distribution and telomere length (kilobases) of peripheral blood leukocytes in patients harboring mutations in telomere-related genes. Telomeres are longer at birth and gradually shorten with aging. TERC, telomerase RNA component.

Figure 2.. Telomere erosion and disease.

Excessive telomere shortening due to genetic effects causing impaired telomere maintenance results in several clinical manifestations. In the bone marrow, telomere shortening affects the hematopoietic stem cell capacity to proliferate and genomic instability, resulting in aplastic anemia and myeloid neoplasms. In the lungs, it appears to affect the AT2 cells, inducing senescence and resulting in interstitial lung disease. In the liver, telomere attrition appears to reduce regeneration and causes metabolic dysfunction, resulting in liver cirrhosis, nodular regenerative hyperplasia, and nonalcoholic steatosis. AT2, alveolar type II epithelial; HSC, hematopoietic stem cell; SASP, senescent-associated secretory phenotype.