Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells

Abstract

Androgens have been used in the treatment of bone marrow failure syndromes without a clear understanding of their mechanism of action. Blood counts of patients with dyskeratosis congenita or aplastic anemia with mutations in telomerase genes can improve with androgen therapy. Here we observed that exposure in vitro of normal peripheral blood lymphocytes and human bone marrow-derived CD34 ؉ cells to androgens increased telomerase activity, coincident with higher TERT mRNA levels. Cells from patients who were heterozygous for telomerase mutations had low baseline telomerase activity, which was restored to normal levels by exposure to androgens. Estradiol had an effect similar to androgens on TERT gene expression and telomerase enzymatic activity. Tamoxifen abolished the effects of both estradiol and androgens on telomerase function, and letrozole, an aromatase inhibitor, blocked androgen effects on telomerase activity. Conversely, flutamide, an androgen receptor antagonist, did not affect androgen stimulation of telomerase. Down-regulation by siRNA of estrogen receptor-␣ (ER␣), but not ER␤, inhibited estrogen-stimulated telomerase function. Our results provide a mechanism for androgen therapy in bone marrow failure: androgens appear to regulate telomerase expression and activity mainly by aromatization and through ER␣. IntroductionTelomere attrition has been associated with the process of normal aging and as etiologic of aneuploid malignancies (in mouse "knockout" models) and of a variety of human diseases (due to mutations in relevant genes). 1 Telomeres consist of T 2 AG 3 repeats and proximate proteins located at the end of chromosomes that serve to prevent recombination, end-to-end fusion, and activation of DNA damage responses. 2 As DNA polymerase is unable to fully duplicate telomeres during cell divisionthe "end replication problem" 3 -telomeres are eroded until reaching critically short lengths, signaling the cell to cease proliferation (cellular senescence) and apoptosis. 2 To maintain telomeres, some highly proliferative cells, including hematopoietic progenitor and stem cells, express telomerase (TERT), a specialized reverse transcriptase capable of adding DNA repeats to the 3Ј end of telomeric leading strand using an RNA molecule (TERC) as a template. Telomerase also is expressed in the majority of malignant cells of many tissues. 4 Abnormal telomere maintenance is a feature of a variety of human diseases. Dyskeratosis congenita, a constitutional type of aplastic anemia, is caused by mutations in genes involved in telomere maintenance (DKC1 is mutated in X-linked dyskeratosis congenita 5,6 ; TERC, TERT, and TINF2 are mutated in autosomal dominant dyskeratosis congenita [7][8][9] ; and TERT, NOP10, and NHP2 are mutated in autosomal recessive dyskeratosis congenita 10,11 ). Mutations in TERT and TERC also are genetic risk factors for acquired aplastic anemia. 12,13 Although most acquired aplastic anemia is the result of an immune process destroying hematopoietic stem and progenitor cells, 14 predisposit...

Sexual dimorphism in cancer

“…These two diseases manifest telomere dis-function, bone marrow failure due to hematopoietic stem cells impairment and are linked to cancer development. Molecularly, in primary hematopoietic cells, androgens induce telomerase expression through aromatasedependent conversion of testosterone into estrogen and ERα activation 38 .…”

TERTrific hormones promote hematopoiesis

“…Mutations in several telomere maintenance proteins, including TERT, result in a genetic marrow failure syndrome, dyskeratosis congenita, and have been shown to increase the risk of developing acquired bone marrow failure and acute myeloid leukemia. 3,4 In sum, these observations highlight a critical role for telomere maintenance and intact TERT function in the regulation of hematopoiesis.…”

“…3 This specific GVT effect is thought to be either directed against antigens with a tissue-restricted distribution (on hematopoietic cells in case of hematologic malignancies) or specifically preferentially expressed on tumor cells. 4 Minor histocompatibility antigens (mHAgs) are polymorphic peptides encoded by genes located throughout the human genome, which can be presented by the major histocompatibility complex (MHC) molecules and recognized as a foreign antigen by T lymphocytes of a certain donor. 5 These peptides can induce both donor-anti-host GVHD and GVT reactions, depending on their expression on both the nonhematopoietic cells and on normal and malignant hematopoietic cells of the recipient, respectively.…”

Neuro-endocrine-immune Crosstalk and Implications for Cancer Therapy

“…Recent preclinical data suggests that one potential explanation is that androgens may act by restoring telomerase expression in hematopoietic cells. Exposure of normal human bone-marrow derived CD34+ cells and of peripheral blood lymphocytes from patients heterozygous for telomerase mutations to androgens increased telomerase activity in one study [78]. This effect was abolished by letrozole, an aromatase inhibitor, but not by flutamide, an androgen receptor antagonist, suggesting that stimulation of telomerase activity by androgens is regulated mainly by aromatization [78].…”