During our Scientific Summit this past July, Abstract Awards were given to three researchers for their submitted work in three categories. Abstract awards are often given to recognize research excellence and help researchers develop professionally. Once again, we wanted to applaud these researchers for their work and share them with our wider community. Team Telomere requested each researcher at our Summit provide both their full original abstract and one written in general language, called a ‘lay summary.’ Keep reading below to see both versions from each awardee.
Award: Best Poster
Awardee: Dr. Enrico Mingardo
Poster Title: “A model of the dynamics of individual telomere lengths.”
Lay Summary: We developed a computer model to predict how telomere lengths change over time. In the future, this might enable us to predict the impact of different interventions and medications on telomere length changes.
Abstract: Long-read telomere sequencing allows for the accurate measurement of the length of individual telomeres. This method has the potential to greatly increase our knowledge of telomere length dynamics on the individual telomere level. However, due to the complex interplay of replication rates, telomere loss during replication, and Telomerase activity, interpreting and quantifying hypotheses of the underlying mechanisms responsible for observed changes in individual telomere lengths is not trivial. Here, we present a model and simulation of the dynamics of individual telomere lengths in human cell culture models. The simulation is directly integrated with the Telo-seq telomere sequencing workflow recently published by Schmidt et al., supporting both the non-mapping route (when a telomere-to-telomere reference genome is not available) as well as the mapping route (when a telomere-to-telomere reference genome is available) of the workflow. Given an initial cell count and Telo-seq measurement, our simulation constructs a model of the cell population that reflects these measurements. Given parameters such as replication rates, telomere loss per cell division, and Telomerase activity, we then forward-simulate the cell population for the duration of the experiment. A final cell count and Telo-seq measurement at the end of the experiment are then compared to the results of the simulation. We present a method based on Approximate Bayesian Computation (ABC) to estimate probability distributions of the unknown model parameters that can explain the Telo-seq measurements. Our method allows us to leverage telomere sequencing to evaluate difficult-to-test hypotheses about individual telomere length dynamics.
Award: Best of Translational Abstracts
Awardee: Dr. Christopher Sande
Abstract Title: “DNA Damage Response Constrains Cell Growth and Drives Clonal Hematopoiesis in Telomere Biology Disorders.”
Lay Summary: People with telomere biology disorders (TBDs) are predisposed to low blood counts and have an increased risk of blood cancers. To better understand why people with TBD develop these problems, we looked for gene mutations in the blood and bone marrow of 160 children and adults with TBD. About 2 out of every 5 had new mutations in their blood cells, which is higher than the general population, and these mutations most often disrupted important genes (most commonly ATM) that affect how cells respond to shortened telomeres and DNA damage. Additional testing on cells from people with TBD showed that DNA damage response is hyperactive in TBD cells, causing them to grow more slowly and stop dividing, but using a drug to simulate mutations in the gene ATM improved cell growth. Future studies are needed to learn whether a similar treatment could improve cell counts and organ dysfunction associated with telomere shortening.
Abstract: Telomere biology disorders (TBD) are genetic diseases that result from defects in telomere maintenance. Patients with TBD often experience bone marrow failure, various systemic complications, and an increased risk of myeloid neoplasms. To better understand the factors underlying hematopoietic outcomes in TBD, we comprehensively evaluated acquired genetic alterations in hematopoietic cells from 160 pediatric and adult TBD patients. Overall, 42% of patients (67 of 160; 22.2% of children and 51.9% of adults) had clonal hematopoiesis. Recurrent somatic alterations included mutations in telomere maintenance genes (4.8% of evaluable patients), spliceosome mutations (7.3%, mainly U2AF1 p.S34), and chromosomal alterations (18.3%), including 1q gain (6.1%). Somatic mutations in genes involved in DNA damage response (DDR) were identified in 14% of patients, including 16 loss-of-function mutations in ATM in 9 patients. We used single-cell transcriptomics to explore gene expression changes in TBD and found significant upregulation of ATM-dependent DDR pathway in TBD hematopoietic stem and progenitor cells. Meanwhile, pathways associated with proliferation, G1-S transition, and translation were downregulated, consistent with DDR-induced senescence. Studies in TBD patients’ fibroblasts showed the activation of the ATM pathway, cell cycle arrest, and enhanced deposition of DDR factors in conjunction with dysfunctional telomeres. Pharmacologic ATM inhibition, modeling the effects of somatic ATM mutations, improved cell fitness in vitro by allowing cells to bypass DDR-mediated senescence without inducing chromosomal instability. Our results suggest that ATM-dependent DDR induced by telomere dysfunction is a key contributor to disease pathogenesis in TBD and suggest dampening hyperactive ATM-dependent DDR as a potential therapeutic intervention.
Award: Best of Clinical Abstracts
Awardee: Dr. Luiz Fernando Bazzo Catto
Abstract Title: “Clinical and molecular features associated with immunodeficiency in telomere biology disorders.”
Lay Summary: Telomere Biology Disorders (TBD) are caused by genetic mutations affecting telomeres, leading to excessive shortening. These disorders are linked to various health issues such as bone marrow failure, liver, and lung fibrosis. While immunodeficiency has been observed in severe cases of one TBD subtype called dyskeratosis congenita, it hasn’t been well studied across different TBD types and in large groups of patients. The study reviewed clinical records of 88 TBD patients and analyzed laboratory data including blood counts and immune cell levels. They defined immunodeficiency based on low levels of certain immune cells. The most common gene mutations observed were TERT and TERC. About 36% of patients experienced significant infections, categorized as opportunistic, recurrent, or requiring hospitalization. Different types of immunodeficiency were associated with specific infection patterns. Interestingly, certain mutations were linked to decreased immune cell counts. In summary, the study highlights that immunodeficiency is common among TBD patients and is associated with a higher risk of significant infections. This underscores the importance of understanding and addressing immunodeficiency in the management of TBD.
Abstract: Telomere biology disorders (TBD) result from germline mutations in telomere associated genes that cause excessive telomere shortening. TBD are associated with bone marrow failure, liver and lung fibrosis. Immunodeficiency has been described in the severe phenotype of dyskeratosis congenita, but is not well characterized in broad spectrum and in large cohorts of TBD patients. We report the clinical and molecular features of immunodeficiency in TBD. Clinical records were reviewed for 88 TBD patients. Laboratory data included: blood counts, B, T and NK subsets, and immunoglobulin levels. A significant infection was defined as the presence of opportunistic, recurrent, and/or infections that required hospitalization. Immunodeficiency was defined by CD8 ≤ 0.178 cell/µL, CD4 ≤ 200 cells/µL, and CD19 ≤ 60 cells/µL. TERT and TERC were the most prevalent germline mutations. Thirty-two patients experienced clinically significant infections (36%), categorized as opportunistic (n=7, 8%), recurrent (n=15, 17%), and those requiring hospitalization (n=20, 22%). CD4 immunodeficiency correlated with infections requiring hospitalization, CD8 immunodeficiency with opportunistic infections and those requiring hospitalization, and CD19 immunodeficiency with recurrent infections. Additionally, decreased absolute lymphocyte count was correlated with solid cancer. No relationship was found between underlying germline mutation and immunodeficiency, but splicing factor somatic mutations were associated with decreased CD3 and CD8 counts. In conclusion, immunodeficiency is common and is associated with increased risk of clinically significant infections.