Heritable mutations in the genes that encode the three minimal components of the human telomerase complex, hTERT, hTERC and DKC are known to give rise to Dyskeratosis Congenita (DC), a rare disorder characterized by skin pigmentation abnormalities, nail dystrophy and leukoplakia. Telomeres in leukocytes of patients with DC are invariably very short and patients typically succumb to consequences of bone marrow failure, pulmonary fibrosis or malignancies. Other genetic defects including mutations in the telomeric protein TINF2 are also known to give rise to DC. However, not all individuals with mutations in “telomere maintenance” genes such as TERT, TERC, DKC and TINF2 will develop clinical symptoms during their lifetime and some patients, without clinical signs of DC, present with aplastic anemia (AA) and idiopathic pulmonary fibrosis (IPF). It was previously shown that hypomorphic mutations in hTERT are 3-fold more common in patients with acute myeloid leukemia (AML) than in controls (Calado et al., ASH abstracts 2007 110: 16). Together with the increased incidence of malignancies in DC these observations suggest that telomere dysfunction can trigger dysplastic as well as neoplastic disorders, most likely because progressive telomere loss results in loss of normal cells and thereby selects for cells with defects in the DNA damage checkpoint(s) that are normally triggered when chromosome ends have insufficient telomere repeats. Such cells are expected to have DNA repair defects and their malignant evolution could be facilitated further by telomere dysfunction triggering cycles of chromosome fusions/bridge/breakage before telomerase is eventually upregulated. In view of these considerations and the important role of telomeres in B cell biology (with telomeres being elongated in the germinal centre and memory B cells having longer telomeres than naïve B cells) we postulated that heritable genetic defects in telomere maintenance could predispose to B cell malignancies as well as AML. To test this hypothesis we sequenced TERC and TERT genes in 80 consecutive CLL patients. No mutations in TERC were found. Sequence variants in TERT were identified in 14 patients with one patient, a compound heterozygous, carrying 2 separate mutations. 5 of the 80 CLL patients carried the A279T TERT variant but this allele was also present in ~ 3% of control individuals. This TERT allele did not significantly reduce telomerase activity in telomerase reconstitution experiments measured by TRAP assay. All other TERT sequence variants that we found in CLL appear to be hypomorhic mutations (that reduce but not completely disable telomerase reverse transcriptase activity) and all were previously described in DC, AA, AML and IPF. Two common variants, D441E and A1062T were screened by high throughput dotblotting of DNA from CLL patients and frequencies of 3/142 (2.1 %) and 12/195 (6.2 %) were found respectively. The presumed germline origin of the TERT mutations in CLL needs to be confirmed. Our results indicate that hypomorphic TERT mutations are common in CLL and contribute to disease in over 10% of patients.

Disclosures: Lansdorp:Repeat Diagnostics: founder.

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