Telomere length (TL) both reflects and limits the replicative life span of normal somatic cells. As a consequence, critically shortened telomeres are associated with a variety of disease states. Telomere attrition can be counteracted by a nucleoprotein complex containing telomerase. Mutations in subunits of telomerase, telomerase-binding proteins as well as in members of the shelterin complex have been described both in inherited and acquired bone marrow failure syndromes. Here, we report on a patient with acquired aplastic anemia and a nonsynonymous variation of codon 1062 of the hTERT gene (p.Ala1062Thr) whose substantial and maintained hematologic response to long-term androgen treatment (including complete transfusion independence) was paralleled by a significant and continued increase in TL in multilineage peripheral blood cells. To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo (141 words).
Supplementing the findings from several previous studies, the Cancer Genome Atlas (TCGA) project recently finalized the systematic characterization of CRC resulting in the first tumor dataset with complete molecular measurements at DNA, RNA, and protein levels. The challenge now is to translate these findings into a robust and reproducible CRC classification system linking molecular features of the tumor to precision medicine.
3427 Telomere length both reflects and limits the replicative life-span of normal somatic cells and critically shortened telomeres are associated with a variety of disease states. In patients with aplastic anemia telomere lengths in granulocytes and lymphocytes can be found to be significantly shorter as compared to age-adjusted controls. Telomere shortening in peripheral blood cells therby mirrors telomere shortening in the underlying hematopoietic stem cell reserve, which can be severely diminished in acquired bone marrow failure syndromes. Genetic aberrations such as mutations in the gene for dyskerin or in subunits of the telomerase-complex such as the RNA subunit hTERC or mutations in the human telomerase gene (hTERT) have been described and linked to critically short telomeres found in blood cells. We report here on a 51 year old male patient with moderate aplastic anemia (AA) and a non-synonymous variation of codon 1062 of the hTERT gene (pAla1062Thr). Cells with deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-AP), i.e. cells with a PNH phenotype, were detected (1.2% of erythrocytes, 8% of reticulocytes and 15% of neutrophils). The patient was found to have dramatically shortened telomere length below 1% percentile of normal individuals both in lymphocytes (4.28 +/− 0.02 kbp) and granulocytes (4.14 +/−0.1 kbp). Based on the clinical presentation (i.e. predominance of red blood cell transfusion dependence and thrombocytopenia, but absence of immediate risk e.g. of infections or bleeding) we decided to initiate androgen treatment rather than to initiate standard immunosuppression. The initially red blood cell transfusion dependent and thrombocytopenic patient became completely red blood cell transfusion independent after twelve months of ongoing androgen treatment. A significant proportion of GPI-AP deficient red cells and reticulocytes could no longer be detected and only a very small proportion of GPI-AP deficient granulocytes (<1%) persisted. The clinical and hematological improvement during androgen therapy was mirrored by a continuous and persistent lengthening of telomere length in total peripheral blood mononuclear cells (MNCs) measured by qPCR as well as in both leukocyte subpopulations measured by Flow-FISH. To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo. Disclosures: No relevant conflicts of interest to declare.
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