Genetic and quantitative determinants of telomere length in human hematopoiesis and transplant outcomes

• Applicant: Dr. Nico Gagelmann
• Subject Area: Hematology, Oncology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578901036

This project integrates clinical and mechanistic telomere research to clarify how genetic and quantitative defects in telomere biology shape hematopoiesis and influence outcomes of allogeneic hematopoietic cell transplantation (HCT). The central premise is that chronological age captures graft quality only imperfectly. Telomere length (TL) - a marker of biological aging and stem cell reserve - shows marked variability, particularly in donors aged ≥35 years. At the same time, many rare germline variants in the telomerase reverse transcriptase (TERT) gene remain functionally uncharacterized, although they are linked to short TL, clonal hematopoiesis (CH), and elevated disease risk. Objectives: (1) Establish TL as an independent predictor of allogeneic HCT outcomes in donors ≥35 years and derive actionable TL thresholds for donor selection. (2) Functionally map rare TERT missense variants and examine their associations with TL, CH signatures, myelodysplastic neoplasms (MDS)/leukemia, and mortality in population cohorts. Together, these approaches will define how quantitative (short TL) and qualitative (TERT dysfunction) constraints converge on hematopoietic fitness. Approach Aim 1: Retrospective NMDP cohort (~8,000 donor-recipient pairs, HCT 2002-2019). Donor TL will be measured by standardized qPCR, batch-corrected, and linked to engraftment, immune reconstitution, graft-versus-host disease, relapse, and non-relapse mortality. Outcomes will be modeled using advanced machine learning. Approach Aim 2: High-throughput cell-based telomere elongation assay to functionally classify 1,486 human TERT variants (≥5 biological replicates). Based on these results, a TERT-specific deep learning predictor will be developed and validated. Functional scores will be integrated with population-level data to analyze associations with TL, CH spectra, MDS/leukemia, and mortality (adjusted for age, sex, ancestry, and TL polygenic risk scores). The project will be conducted at the Dana-Farber Cancer Institute, which offers outstanding infrastructure for genomics, functional assays, and clinical analytics. Data will be de-identified, processed reproducibly, and openly shared. Outputs will include SOPs, analysis code, a comprehensive TERT functional atlas, calibrated predictive models, and a web-based TL risk tool for global donor registries. Translational impact: Establish TL as a measurable determinant of donor selection and conditioning intensity; enable identification of “biologically young” older donors; expand the donor pool; and improve long-term outcomes. The project will also provide a robust framework for genetic screening and counseling around germline TERT variants—laying the groundwork for precision and equity in transplantation medicine.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Coleman Lindsley