Telomerase Complex Mutations Research Articles

New trajectories in the treatment of interstitial lung disease: treat the disease or treat the underlying pattern?

A subset of patients with interstitial lung diseases (ILDs), such as rheumatoid arthritis (RA)-associated ILD and chronic hypersensitivity pneumonitis, will experience a disease course similar to patients with idiopathic pulmonary fibrosis (IPF). They also often have a usual interstitial pneumonia (UIP) pattern of fibrosis. Although the standard of care for patients with RA-ILD and chronic hypersensitivity pneumonitis is immunosuppression, the optimal treatment for patients with progressive disease and a UIP pattern remains unknown. Recent research has highlighted shared risk factors, disease behavior and pathobiology between RA-ILD, chronic hypersensitivity pneumonitis and IPF. The presence of a UIP pattern, in both RA-ILD and chronic hypersensitivity pneumonitis, is associated with a worse prognosis. Moreover, genetic risk factors, previously well characterized in IPF, are increasingly being linked to RA-ILD and chronic hypersensitivity pneumonitis. The MUC5B promoter variant rs5705950, telomerase complex mutations and short telomere lengths are also linked to an increased susceptibility to pulmonary fibrosis in RA and chronic hypersensitivity pneumonitis. IPF shares several clinical, genetic and biological features with other ILDs exhibiting the UIP pattern. The optimal pharmacologic management of these patients remains uncertain. Several ongoing trials are evaluating the efficacy of antifibrotic medications in these other diagnoses and may change how we approach ILD treatment.

Telomere Length and Telomerase Complex Mutations Predict Fatal Treatment Toxicity after Stem Cell Transplantation in Patients with Myelodysplastic Syndrome

Introduction: Identifying patients at high risk of fatal treatment toxicity is a central challenge in hematopoietic stem cell transplantation (HSCT). Objective metrics that enable more accurate prediction of non-relapse mortality (NRM) could inform clinical decisions about timing and modality of HSCT. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress. We therefore evaluated the impact of recipient telomere length on clinical outcomes based on treatment intensity in patients with myelodysplastic syndrome (MDS) receiving HSCT.Methods: We used qPCR to measure relative telomere lengths in whole blood DNA samples from 1514 patients who received allogeneic HSCT for MDS and were enrolled in the Center for International Blood and Marrow Transplant Research Repository. Within the cohort, patients age 40 and older were grouped into those with short (<25th), intermediate (25-75th) or long (>75th percentile) telomeres. To evaluate germline determinants of telomere length, we sequenced 7 genes involved in telomere maintenance and mutated in dyskeratosis congenita: TERC, TERT, DKC1, TINF2, NHP2, WRAP53 and CTC1. Putative germline variants were classified as “rare” if the allele frequency was <0.001 in all Genome Aggregation Database (gnomAD) populations.Results: Among patients age 40 and older (n=1267), those with short (HR 1.52, 1.24-1.85, p<0.001) or intermediate (HR 1.35, 1.13-1.61, p<0.001) telomere length had poor overall survival compared with those having long telomeres (Fig 1A). In a competing risks regression model, the adverse effect of shorter telomeres was driven by a significantly higher risk of NRM among patients with short (HR 1.57, 1.20-2.06, p=0.001) and intermediate (HR 1.32, 1.03-1.69, p=0.03) telomere length. The association between telomere length and NRM was evident in patients receiving myeloablative (MAC, p=0.002) but not reduced-intensity conditioning (RIC, p=0.2) regimens (Fig 1B). We observed no association between telomere length and disease relapse in patients receiving MAC or RIC regimens. In a multivariable regression model, the prognostic significance of telomere length was independent of clinical and genetic factors, including age, Karnofsky performance status, hematologic parameters, IPSS-R risk category, donor mismatch, donor age, and TP53 mutation.We identified 40 patients (2.6% of the cohort) with rare germline TERT variants. Patients with rare TERT variants had significantly shorter telomeres than patients with common (p=0.001) or no (p<0.0001) TERT variants and were diagnosed with MDS at an earlier age than patients with common (52.2 vs. 58.4 years, p=0.01) or no (52.2 vs. 57.9 years, p=0.01) TERT variants. The domain distribution of rare TERT variants mirrored that of validated pathogenic germline TERT mutations, primarily affecting the reverse transcriptase and C-terminal extension domains. Rare variants in TERC (0.4%) and DKC1 (0.2%) were also associated with shorter telomeres (p=0.02 and p=0.04, respectively). In total, we identified germline telomerase complex mutations in 49 of 1514 MDS patients (3.2%), even though only 1 patient had a clinical diagnosis of dyskeratosis congenita. Together, patients with telomerase complex mutations had shorter overall survival than those without mutations (unadjusted p=0.008), attributable to a marked increase in the risk of early NRM among those receiving MAC (1 year cumulative incidence of NRM 48% vs. 26%, p=0.03). The impact of shorter telomeres on NRM was similar in patients with and without identified core telomerase complex mutations, suggesting that additional mechanisms of impaired telomere length maintenance may contribute to MDS pathogenesis and outcome.Conclusion: Recipient telomere length is independently associated with overall survival after allogeneic HSCT for MDS. Patients age 40 or older with shorter blood cell telomere length have a significantly elevated risk of early NRM with myeloablative conditioning regimens. Clinically unrecognized germline mutations in the telomerase genes TERT, TERC, and DKC1 define a distinct subset of adult patients with sporadic MDS and short telomeres who have poor transplant outcomes. Together, these results indicate that short telomere length in MDS patients mediates fatal treatment toxicity that may be attenuated by lower intensity conditioning approaches. DisclosuresAntin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

(362) - Clinical Outcomes of Lung Transplantation in Patients With Telomerase Complex Mutations

People with telomerase complex mutations can develop pulmonary fibrosis and progressive respiratory failure. They are also predisposed to myelosuppression, cirrhosis, and malignancy, which may present challenges to successful lung transplantation (LT) due to the myelosuppressive, hepatotoxic, and carcinogenic effects of medications required to maintain allograft function. In this case series we describe the clinical outcomes of 14 LT recipients with telomerase complex mutations.

Hereditary Mutations Are Present As Pathogenic or Predisposition Factors in Otherwise Typical Adult MDS

Familial MDS has been rarely reported, with few cases usually being in the context of early-onset disease and germline (GL) mutations. Patients with familial RUNX1 mutations show thrombocytopenia and progression towards MDS/AML. Similarly, germ line-(GL) CEBPA and GATA2 mutations are associated with MDS/AML. Within typical MDS, late presentation makes it difficult to distinguish hereditary factors from aging or environmental exposures. Only in rare cases, a strong family history may suggest a genetic predisposition.Most of the NGS-based projects focused on discovery of somatic mutations, but it can ]also be used to search for disease prone GL-encoded sequence alterations. For the purpose of this study we hypothesized that in a proportion of seemingly sporadic MDS, known or new GL mutations may be present. They may predispose to disease evolution or constitute a first hit with a long latency, making assessment of penetrance difficult. Because of the tremendous amount of data generated through unbiased cross-sectional approaches and validation needed, we have devised various rational prioritization and analytic strategies: i) we stipulated that genes affected by somatic mutations may also be targets of GL alterations; ii) we screened for alterations in a panel of genes known to constitute predisposing factors to cancer and found in a limited WE NGS study (N=106) to be more frequent than expected in MDS. These genes were included in a somatic targeted panel of 81 genes.In total we have analyzed 459 patients with typical MDS and focused on results of the above described analytic strategies. All identified alterations were independently validated to exclude somatic lesions and technical artifacts. Following sequencing, tier-1 lesions were defined as known disease-prone sequence alterations/mutations, new nonsense/frameshift mutations and highly recurrent missense mutations exceedingly rare in the general population. Tier-2 lesions were defined as missense mutations with general population frequency of <1% in the general population. Among those, the prioritization is according to the frequency and predicted impact on the protein function. For example, among tested genes, we found a total of 73 tier-1 lesions (>1) MDS. Altogether (tier-1/2) we identified 281 non-synonymous GL sequence alterations in 209 cases (45%). Surprisingly, high frequencies of mutations in DNA repair genes (including ATM, ATR or FA genes) were found in heterozygous and even (4 cases) in biallelic configuration. We also identified adult patients with otherwise typical Li-Fraumeni TP53/CHEK2 mutations. In total we found 40 tier-1 FA gene mutations, 7 ATM and 6 telomerase complex mutations and many others. One of FA genes was found to be affected by a novel, recurrent, frameshift GL variant present in 4 cases. Interestingly, the same locus is mutated in 2 non-hematological cell lines and there are proximal somatic mutations reported in that region. Several clinical and molecular associations were found when patients with various tier-1 mutations were studied. For instance, the presence of heterozygous GL mutations in FA/DNA repair genes were associated with somatic deletion of chr.7 or del5q (P<.001).We also classified 208 tier-2 alterations. Among them, we focused our analysis on the most recurrent alterations. Not surprisingly some of the genes frequently affected by tier 1 mutations also showed common tier-2 mutations. Examples include heterozygous tier-2 genes such as, FA genes and ATM found in 9% and 14% patients, respectively. For some of the functionally related genes a combined tier-1/2 analysis was performed. For instance, analysis of telomerase machinery genes included NOP10, POT1, TERT, TERC and DKC1. Surprisingly, out of 5 different variants in TERT found in MDS patients, 2 were canonical, p.H412Y (N=3) and p.A279T (N=3) and reported to be pathogenic in hereditary aplastic anemia. Most frequent SNVs were found in ATM (N=66) and APC (N=20).In conclusion, our results suggest that important GL alterations in cancer predisposition genes can be found in patients with otherwise seemingly sporadic MDS. Some of the genes thought to cause MDS in recessive fashion may contribute to MDS susceptibility in a delayed mode when present in heterozygous configuration. We conclude that already our very limited screen suggests inherited factors may play an important role in the pathogenesis of adult MDS. DisclosuresSekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen Corp: Membership on an entity’s Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity’s Board of Directors or advisory committees.

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Mutations in the telomerase complex (TERT and TR) are associated with pulmonary fibrosis and frequent hematologic manifestations. The aim of this study was to characterize the prognosis of lung transplantation in patients with TERT or TR mutations. Patients with documented TERT or TR mutations who received a lung transplant between 2007 and 2013 in France were identified via an exhaustive search of the lung transplantation network, one expert genetic laboratory, and the clinical research network on rare pulmonary diseases. There were 9 patients (7 men) with TERT (n = 6) or TR (n = 3) mutations who received a single (n = 8) or a double (n = 1) lung transplant for pulmonary fibrosis. Median age was 50 years (range, 35-61 years) at diagnosis and 52 years (range, 37-62 years) at the time of lung transplantation. Thrombocytopenia was present in 7 patients before lung transplantation. After lung transplantation, 6 patients developed myelodysplasia and/or bone marrow failure, directly contributing to death in 4 cases. Anemia was observed in 9 patients, and neutropenia was observed in 3 patients. The median survival after lung transplantation was 214 days (range, 59-1,709 days). Patients with mutations of the telomerase complex are at high risk of severe hematologic complications after lung transplantation, in particular, bone marrow failure. Specific recommendations should be developed for appropriate guidance regarding hematologic risk assessment before transplantation and management of the post-transplantation immunosuppressive regimen.

Telomere length and telomerase complex mutations in pediatric acute myeloid leukemia

Telomere length and telomerase complex mutations in pediatric acute myeloid leukemia

Telomere Length and Telomerase Complex Mutations in Pediatric Acute Myeloid Leukemia

AbstractAbstract 1482Inherited loss-of-function mutations in the telomerase complex gene TERT have recently been implicated as risk factors for acute myeloid leukemia (AML) in adults. The telomerase complex is expressed in highly proliferative cells, and is responsible for maintaining telomeres, which cap the ends of chromosomes and protect genomic DNA from eroding during cell division. Impaired telomerase function can result in extremely short telomeres, which limits the proliferative capacity of progenitor cells, and can also lead to chromosomal instability, thus predisposing to malignant transformation. In pediatric AML, the frequency of such mutations, and the association of telomere length with cytogenetic, molecular, and clinical characteristics and outcome, are unknown.In a cohort of 168 pediatric AML patients, we determined the frequency of telomerase complex gene mutations and leukemic cell telomere length, and correlated this with prognostic cytogenetic characteristics (inv(16), t(8;21), MLL rearrangements, normal karyotype, other aberrations), molecular aberrations (CEBPA double mutations, NPM1 mutations, FLT3/ITD, WT1 mutations), clinical characteristics, and outcome.No mutations were present in TERC. Three heterozygous variants in TERT, E327D, T726M, and A1062T, were identified in eight of 168 pediatric AML patients (carrier frequency 0.048). In three of six patients carrying A1062T, remission material was available, in which germ-line origin of the variant was confirmed. The variants E327D and T726M were absent, but A1062T was present in a cohort of 406 geographically matched controls (carrier frequency 0.049). Telomerase activity, as determined by TRAP assay in reconstitution experiments, of the novel E327D variant was unaffected, as was the previously published activity of T726M; the earlier reported activity of A1062T was reduced to 60%.Telomere length of leukemic cells was not associated with age, sex, prognostic cytogenetic subgroup, complex karyotype, or expression levels of telomerase and shelterin complex genes. However, patients carrying the high-risk molecular aberration FLT3/ITD had significantly shorter telomeres than did patients with favorable NPM1 mutation or CEBPA double mutations. Telomere length was not associated with overall survival, event-free survival, or cumulative incidence of relapse.We conclude that, in pediatric AML, telomerase complex mutations do not confer a risk for leukemia development, and although short telomeres correlate with the high-risk molecular aberration FLT3/ITD, telomere length of leukemic cells obtained at diagnosis does not correlate with adverse outcome in this pediatric AML cohort. Disclosures:No relevant conflicts of interest to declare.

Clinical Impact of TERT A1062T Mutations in Younger Patients with Acute Myeloblastic Leukemia

AbstractAbstract 1381▪▪This icon denotes a clinically relevant abstract Background:Acute myeloid leukemia (AML) is a heterogenous disease. In addition to cytogenetic aberrations, somatic mutations in several genes (e.g. NPM1, FLT3, DNMT3A, WT1) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Recently, it was shown that also germline mutations in the gene encoding the reverse transcriptase component of the human telomerase complex (TERT) are associated with AML and occur with a frequency of approximately 3–5% (Calado et al. Proc Natl Acad Sci USA 2009; 106:1187–92). These mutations lead to a reduced enzymatic activity of the telomerase complex. The most frequent of these mutations is an G>A conversion in codon 1062 in exon 15 of TERT which leads to an alanine>threonine substitution (A1062T). Telomerase complex mutations had previously been described in patients with bone marrow failure or other organ dysfunction such as liver cirrhosis or pulmonary fibrosis. The impact of such mutations on the clinical course and prognosis of AML patients, however, is unknown. Aims:We wanted to analyze the clinical and prognostic impact of the most common TERT mutation A1062T in younger AML patients treated within two prospective multicenter trials. Methods:The mutational hotspot in exon 15 of the TERT gene was analyzed by direct sequencing in 420 patients (age 16–60 years) with AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations/aberrations in the genes NPM1, FLT3, WT1 and DNMT3A. Median follow up was 79 months. Results:Fifteen of the 420 analyzed patients (3.3%) carried a TERT A1062T mutation. In the four patients of whom remission bone marrow or blood samples were available, the mutation was also detected in complete remission suggesting a germline origin of the mutation. Patients with TERT mutations had a trend (p = 0.06) towards less favorable (13% vs. 42%) and more intermediate-2/adverse karyotypes/genotypes (60% vs. 31%) according to the ELN classification. Other clinical and molecular parameters did not differ from wildtype patients. In univariate analysis, patients with TERT mutations had a significantly inferior overall survival (OS) compared to wildtype patients (HR 2.31; 95% CI 1.29 – 4.13, p = 0.005; 3year OS 20% vs. 46%). Also, in multivariate analysis TERT mutations were an independent negative factor for OS when analyzed together with age, leukocytes/peripheral blasts, platelets, extramedullary disease, de novo vs. secondary AML, ELN risk classification, WT1 SNP rs16754 and mutations in NPM1, FLT3 and DNMT3A. In addition to a high relapse rate, TERT mutated patients also showed a high rate of treatment related mortality: 5/15 (33%) of the mutated patients died during induction therapy or in CR as compared to 62/405 (15%) of the wildtype patients (p = 0.07). Of note, three of four TERT mutated patients who received an allogeneic stem cell transplantation in first CR died in CR. Therefore, we also analyzed treatment related toxicity during induction therapy. In the TERT mutated patients, 14/15 (93%) suffered from non-hematological/non-infectious grade 3 or 4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wildtype patients (p = 0.006). In multivariate analysis, TERT mutations were an independent risk factor predicting for adverse events during induction (OR 9.6; 95% CI 1.24 – 75.23, p = 0.031) when analyzed together with age, ELN risk classification, other gene mutations, blood counts, extramedullary disease, ECOG performance status, response to first induction therapy, and de novo vs. secondary AML. Conclusions:TERT A1062T mutations are an independent negative prognostic factor in younger patients with AML. These mutations seem to predispose AML patients to treatment-related toxicity and mortality. Disclosures:No relevant conflicts of interest to declare.

Erosion of telomeric single‐stranded overhang in patients with aplastic anaemia carrying telomerase complex mutations

Loss-of-function mutations in telomerase complex genes reduce telomerase activity and shorten overall telomere length in leucocytes, and they can clinically manifest as bone marrow failure (aplastic anaemia and dyskeratosis congenita) and familial pulmonary fibrosis. Telomeres are constituted of double-stranded tandem TTAGGG repeats followed by a 3' G-rich single-stranded overhang, a crucial telomeric structural component responsible for the t-loop formation. We investigated the length of telomeric overhangs in 25 healthy individuals from 0 to 76 years of age, 16 patients with aplastic anaemia, and 13 immediate relatives using a non-denaturing in-gel method and the telomere-oligonucleotide ligation assay. Telomeric overhang lengths were constant from birth to eighth decade of life in healthy subjects, in contrast to overall telomere length, which shortened with ageing. Most patients with marrow failure and a telomerase gene mutation showed marked erosion of telomeric overhang associated with critically short telomeres; in other aplastic patients with normal genotypes, normal overall telomere lengths and who responded to immunosuppressive therapy, telomeric overhangs were maintained. Telomeric overhang erosion does not participate in physiological ageing but support a role for eroded telomeric overhangs and abnormal telomere structure in pathological shortening of telomeres, especially caused by loss-of-function telomerase mutations. Disrupted telomere structure caused by short telomeric overhangs may contribute to the mechanisms of abnormal haematopoietic compartment senescence and chromosomal instability in human bone marrow failure.

Evidence for T-Cell Oligoclonal Expansion in Aplastic Anemia Associated with Telomerase Complex Mutations: Pathophysiological and Clinical Implications.

Aplastic anemia is characterized by peripheral blood pancytopenia and a hypocellular bone marrow. In the majority of patients, bone marrow destruction is immune-mediated by a type-1 T cell response, dominated by oligoclonal expansion of CD8+ cells and targeting hematopoietic stem cells. Some patients with acquired aplastic anemia are heterozygous for mutations in genes encoding the major components of the telomerase complex, telomerase reverse transcriptase (encoded by TERT; Yamaguchi et al., N Engl J Med 2005; 352:1413) and the RNA component (encoded by TERC; Fogarty et al., Lancet 2003; 362:1628). These mutations lead to shortened telomeres of leukocytes, low telomerase activity and reduced hematopoietic function. Relatives carrying the same mutations also have short telomeres and reduced hematopoietic function, but they do not inevitably develop overt marrow failure. In contrast, dyskeratosis congenita, a constitutional type of marrow failure, is caused by mutations in TERC (autosomal dominant type) or in the DKC1 gene, which encodes an additional component of the telomerase complex, dyskerin. In addition to marrow failure, patients with dyskeratosis congenita also often have physical anomalies, such as leukoplakia, nail dystrophy, and hyperpigmentation as well as hepatic or pulmonary fibrosis. In dyskeratosis congenita, family members bearing the genetic mutation present variable degrees of physical abnormalities or organ damage. However, in patients with acquired aplastic anemia carrying telomerase mutations without physical anomalies, it is unclear whether these mutations are sufficient for the development of marrow failure. We hypothesized that telomerase complex mutations reduce the size of the hematopoietic stem cell compartment and affect its regenerative capacity, making carriers more vulnerable to environmental insults or autoimmune damage. We analyzed the distribution of the T-cell repertoire (T-cell receptor [TCR] Vβ subfamily) and expansion of particular Vβ subsets by flow cytometry in peripheral blood of six aplastic anemia patients carrying telomerase complex mutations (five with TERT mutations, one with a TERC mutation), two patients with Fanconi anemia, and 15 healthy subjects. The expression of 22 Vβ subfamilies were evaluated in CD8+CD28− cells, and expansion was defined when the percentage of a given Vβ subfamily was above two standard deviations based on the control group (Risitano et al. Lancet 2004; 364:355). We also evaluated interferon-γ levels in serum of nine telomerase mutant patients and 10 controls by ELISA. Expanded Vβ subsets were observed in all six aplastic patients carrying telomerase complex mutations analyzed. Five patients (with TERT mutations) had two clones expanded and one (with TERC mutation) showed three overrepresented clones. The Vβ subsets 9, 13.6, 17, and 20 were expanded in more than one patient. Oligoclonal Vβ expansion was not observed in Fanconi anemia. Telomerase mutant patients also had significantly increased interferon-γ serum levels in comparison to controls (27 pg/mL; range, 0–95 vs. 7.6, 0–16, respectively; P<0.02). These results indicate that an immune process targeting hematopoiesis may operate in patients carrying telomerase complex gene mutations. Limited responsed to immunosuppression may reflect the poor hematopoietic reserve rather than a nonimmunologic mechanism of marrow destruction.

Sex Hormones Up-Regulate Telomerase Activity of Normal Human Hematopoietic Cells and Restore Telomerase Activity in Carriers of Telomerase Complex Mutations.

Mutations in components of the telomerase complex (TERT and TERC) are risk factors for acquired aplastic anemia. Telomerase is a reverse transcriptase responsible for the maintenance of telomeres, repetitive nucleotide sequences capping the chromosome ends. Patients with marrow failure with TERT or TERC mutations have low telomerase activity, short telomere length in leukocytes, reduced hematopoietic function, and they do not respond adequately to immunosuppressive therapy. The constitutional aplastic anemia dyskeratosis congenita is also caused by mutations in TERC (autosomal recessive type) or in an additional component of the telomerase complex, dyskerin, encoded by the DKC1 gene (X-linked type). The majority of patients with dyskeratosis congenita and some patients with acquired aplastic anemia benefit from androgen therapy, but the mechanism by which this hormone stimulates hematopoiesis is not well understood. We investigated whether sex hormones stimulated telomerase activity in hematopoietic tissue. Peripheral blood lymphocytes from either healthy controls or mutation carriers were cultured with phytohemagglutinin and interleukin-2 for 1–7 days in the presence of methyltrienolone, estradiol, hydroxycortisone, and/or tamoxifen. Telomerase enzymatic activity was measured using a fluorescent telomere-repeating amplification protocol (TRAP), and TERT mRNA expression was assayed by real-time PCR. Androgens and estradiol up-regulated telomerase activity in lymphocytes from normal subjects in a dose-dependent fashion (controls, 124±24 total product generated [TGP] units per reaction; methyltrienolone 1 μM, 242±16 TGP units/reaction; methyltrienolone 10 μM, 757±87 TGP units/reaction; P<0.01). Increased telomerase activity correlated to higher TERT mRNA levels (P<0.05). Steroidal effects on telomerase activity were neutralized by tamoxifen, an estrogen antagonist. TERT mutation carriers had lower telomerase activity compared to controls (P<0.05), but their enzymatic function was restored to normal levels when cultured with methyltrienolone. As a control, hydrocortisone at 1 μM inhibited telomerase activity without influencing cell cycle or inducing apoptosis. We also investigated the effects of androgen on hematopoietic progenitor cells. Bone marrow CD34+ cells from normal subjects were immunomagnetically separated and cultured for eight days in StemSpan supplemented with Flt-3 ligand, stem cell factor, and interleukins 3 and 6, in the presence methyltrienolone. Up-regulation of telomerase activity was observed in CD34+ cells cultured with methyltrienolone (P<0.05), the increase correlated with greater cell numbers, a higher proportion of CD34+ cells after eight days of culture (from 10% to 15% at 10 μM methyltrienolone and to 19% at 100 μM), without changes in cell cycle or cell differentiation, based on CD45, CD71, and CD33 expression. These results indicate that sex hormones stimulate TERT expression via the estrogen receptors, leading to increased telomerase activity in hematopoietic cells and increased proliferation of hematopoietic progenitors. Androgens were able to restore telomerase activity to normal levels in TERT mutation carriers. Sex hormone effects on telomerase in normal cells may have implications for the normal aging process and in hematological malignancy (leukemic cells have high telomerase activity), and our results suggest that androgens might be useful in the treatment of patients bearing telomerase complex mutations.