Characterization of hTERT Mutations in Bone Marrow Failure Syndromes

Inherited bone marrow failure (IBMF) syndromes are a group of disorders associated with insufficient production of hematopoietic cells and are characterized by a predisposition for malignancies including myelodysplastic syndrome (MDS) and acute leukemia (AML). A majority of these disorders including aplastic anemia (AA) and dyskeratosis congenita (DKC) are characterized by defects in telomere maintenance and excessively short telomeres. Studies have demonstrated an association between shortened telomeres, advanced disease and increased risk of developing blood cancers. Heterozygous mutations in the gene encoding the telomerase protein component, hTERT, are seen in 5-15% of patients with IBMF, resulting in short telomeres and advanced disease. Loss of function of one autosomal copy of hTERT is sufficient to reduce telomerase levels and accelerate telomere attrition. The degree of inactivity subsequent disease phenotype among the mutations is variable. However, the impact of telomerase mutations and shortened telomeres on disease progression and response to therapeutics is not well understood.To understand the biochemical properties and cellular consequences of mutant hTERT expression we have generated expression constructs in various cellular models in order to investigate the function of 7 distinct hTERT mutants identified in patients with AA, DKC and MDS/AML . These mutations have been identified in patients with family history or clonal evolution of disease and are all loca...
Source: Blood - Category: Hematology Authors: Tags: 508. Bone Marrow Failure Source Type: research