Molecular Oncology Programme

Telomeres and Telomerase Group

Group Leader:  María A. Blasco
Research highlights
Fighting aplasic anaemia using a therapy designed to delay ageing

Aplasic anaemia is a rare, potentially fatal disease of the blood, by which the bone marrow is unable to generate blood cells at the appropriate pace. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of haematopoietic stem and progenitor cells owing to very short telomeres due to mutations in telomerase and other telomere components. An abnormal telomere shortening is also described in cases of acquired aplasic anaemia. We have tested the efficacy of our telomerase gene therapy, originally designed to delay ageing, in two independent mouse models of aplasic anaemia due to short telomeres. We found that a high dose targets the bone marrow compartment, including haematopoietic stem cells. Telomerase treatment following telomere attrition in bone marrow cells rescues aplasic anaemia and mouse survival. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. Our telomerase gene therapy represents a novel therapeutic strategy to treat aplasic anaemia provoked or associated with short telomeres.

Mice with hyper-long telomeres and unaltered genes

Telomere length is genetically determined, but in the past we were able to generate mouse embryonic stem (ES) cells with telomeres twice the size of normal ones. We have now used such ES cells with ‘hyper-long’ telomeres, traceable thanks o the co-expression of green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We showed that chimaeric mice contain GFP-positive cells – bearing hyper-long telomeres – in all mouse tissues (FIGURE 1), display normal tissue histology, as well as normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells manage to retain longer telomeres as the mice age. These chimaeric mice also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. Cells with hyper-long telomeres are longitudinally maintained or enriched with age in highly renewing compartments (i.e. blood). We demonstrated that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as telomerase overexpression.

Telomeric RNAs are essential to maintain telomeres

Despite their especially compact structure, which is difficult to access, telomeres transcribe information like the rest of the DNA generating long non-coding RNAs known as TERRA. Deciphering the role of TERRA was one of the unsolved issues of telomere biology in the past decade. This was, in part, due to a lack of knowledge on the TERRA loci, which had prevented functional genetic studies. We had already shown that mouse TERRA arise mainly from the subtelomere of chromosome 18 and to a lesser extent from the subtelomere of chromosome 9. We have now described that long non-coding RNAs with TERRA features are transcribed from the human 20q and Xp subtelomeres. We used the CRISPR-Cas9 technology to delete the 20q locus, which resulted in a dramatic decrease in TERRA levels. The deletion of the Xp locus, on the contrary, does not lead to decreased TERRA levels. These findings demonstrate that, although human TERRA arise from two loci, the 20q locus is the main origin of human TERRA. Thus, both in mice and in humans, TERRA arise from one, or at most two loci (FIGURE 2). Ablation of 20q-TERRA in human cells results in a dramatic loss of telomere sequences and in the induction of a massive DNA damage response. These latter findings represent the first demonstration, in any organism, of the essential role of TERRA in the maintenance of telomeres.