Androgen derivatives improve blood counts and elongate telomere length in adult cryptic dyskeratosis congenita

Abstract

Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome-related mutations. Seven TERC or TERT-mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS-related mutations were detected. Pending longer follow-up, treatment with AD seems to represent an efficient and safe therapy for DKC patients.

Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita

“…ADs are, e.g., able to activate the erythropoietin receptor in progenitor cells [29]. Of note, all effects including telomere elongation were observed in a relatively short time, in line with previous studies reporting clinically relevant response to AD treatment within the first three months in most cases [22,23].…”

“…Treatment with ADs is able to stimulate telomere elongation in patients with TERC or TERT mutations, as observed in our work [22] and in previous studies [18][19][20]. We therefore tested whether a relatively short treatment with ADs could cause an increase in telomere length in vitro in BM-MNCs.…”

“…Thus, haploinsufficiency of telomerase components in most patients with DKC can be counterbalanced by increasing telomerase activity via stimulation of TERT expression. Recently and in line with these studies [18][19][20], we could show that long-term treatment with danazol and oxymetholone improved blood counts and elongated telomere length in patients with DKC and mutations in TERT and TERC genes [22]. However, so far, prospective clinical studies comparing different AD are missing, mostly due to the rareness of this disease and the clinical diversity of the affected patients.…”

Epigenetic Clocks Are Not Accelerated in COVID-19 Patients

“…Flow-FISH analysis of telomere length was carried out as previously described [27,28]. Briefly, vital frozen mononuclear cells from peripheral blood were mixed with a FITC labeled telomere specific (CCCTAA)3-peptide nucleic acid FISH probe (Eurogentec, Seraing, Belgium) for DNA-hybridization followed by DNA counterstaining with LDS 751 (Sigma, St. Louis, MO, USA).…”

Epigenetic clocks are not accelerated in COVID-19 patients

“…A recent study indicated that in leukocytes of COVID-19 patients telomere attrition below the 10 th percentile is more frequent than in healthy controls (Froidure et al, 2020), however the results of this study might be affected by the lymphopenia observed in COVID-19 patients (Benetos et al, 2020). To further investigate if this alternative biomarker for biological age is accelerated, we analyzed telomere length in lymphocytes of 19 COVID-19 patients with Flow-FISH, as described in detail before (Ferreira et al, 2020; Kirschner et al, 2020). In comparison to the telomere length distribution of 356 healthy controls (Werner et al, 2015) there was overall no evidence for significant telomere attrition in COVID-19 patients (Figure 2C,D).…”