Defective Telomerase in Familial Myelodysplasia and Leukemia

Myelodysplastic syndromes (MDS) comprise a diverse range of hematological conditions, all of which involve impaired or disturbed hematopoiesis, cytopenias, marrow dysplasia and the risk of progression to acute myeloid leukemia (AML). MDS and AML are believed to involve a multi-step process arising within bone marrow stem cells, but the specific defects responsible remain poorly understood. In cases of inherited, familial forms of the disease two genes have been implicated: the hematopoietic transcription factors CBFA2 (core binding factor a2) and CEBPA (CCATT box enhancer binding protein a) and these account for only a small number of the familial cases so far reported. The uncharacterized families represent an ideal resource for identifying the primary pathology of the disease. In this study we have screened 21 families where MDS/AML appears to be familial for mutations in the telomerase enzyme components TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase). In two families, we have identified novel mutations in TERC and in another two we have identified mutations in TERT directly resulting in MDS/AML. Functional analysis has demonstrated that all mutations adversely impact telomerase activity in vitro and affected individuals have short telomeres (see Table 1 for summary). These results have several important implications: First, they identify a novel genetic pathway (defective telomere maintenance) that can lead to familial MDS/AML; second, they suggest that TERC and TERT act as tumour suppressors and; finally, they have implications for the biology, treatment and screening regimen for de novo cases of MDS/AML.

Table 1 – Summary of clinical and molecular analyses of four families with MDS/AML