The many faces of the helicase RTEL1 at telomeres and beyond.

Regulator of telomere elongation 1 (RTEL1) is known as a DNA helicase that is important for telomeres and genome integrity. However, the diverse phenotypes of RTEL1 dysfunction, the wide spectrum of symptoms caused by germline RTEL1 mutations, and the association of RTEL1 mutations with cancers suggest that RTEL1 is a complex machine that interacts with DNA, RNA, and proteins, and functions in diverse cellular pathways. We summarize the proposed functions of RTEL1 and discuss their implications for telomere maintenance. Studying RTEL1 is crucial for understanding the complex interplay between telomere maintenance and other nuclear pathways, and how compromising these pathways causes telomere biology diseases, various aging-associated pathologies, and cancer.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure. STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. RESULTS: The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.