Extreme telomere erosion in ATM-mutated and 11q-deleted CLL patients is independent of disease stage.

Chronic lymphocytic leukaemia (CLL) is considered to arise from a failure of apoptosis and an accumulation of CD5+CD23+ mature B-cells, although significant levels of cell division underlie the clonal growth of these cells. This is apparent from deuterated water incorporation experiments1 as well as telomere erosion.2, 3, 4 We have recently shown that the telomere erosion observed in CLL patients is extensive and can result in the loss of telomere function resulting in telomere–telomere fusion events, some of which were clonal;5 this work also revealed telomeric loss of heterozygosity as well as large-scale genomic rearrangements that were concomitant with telomere dysfunction. Telomere dysfunction may therefore account for clonal evolution and the occurrence of large-scale genomic rearrangements, including the loss of 17p and 11q, that confer a poor prognosis and are associated with short telomeres.3 Short telomeres and telomeric DNA damage are also associated with the development of resistance to DNA damage-induced apoptosis.6 The telomere dynamics described in CLL are indistinguishable from those observed experimentally in fibroblast cells undergoing a telomere driven ‘crisis’ in culture following the abrogation of the p53 pathway.5 In this situation, the loss of cell cycle checkpoints in response to DNA double-strand breaks (DSBs) facilitates the ongoing cell division beyond the point that would normally trigger telomere-dependent replicative senescence. It is clear from these in vitro studies that there is a subtle distinction between the length of telomere that elicits a cell cycle checkpoint response, triggering p53-dependent replicative senescence or apoptosis and the shorter telomeres that are capable of fusion in cells undergoing ‘crisis’.5 Based on these observations, we hypothesised that in order for CLL cells to achieve substantial telomere erosion and dysfunction they must be compromising in their ability to mediate cell cycle checkpoints in response to the DSBs that arise from telomere shortening and uncapping.7 A key mediator of the cellular response to DSBs is the protein encoded by the ATM tumour-suppressor gene, mutations that confer a marked defect in cell cycle checkpoints and subtle defects in the ability of the cells to repair DSBs.7 ATM plays a key role in DNA damage signalling by p53 specifically in response to DSBs, including those observed at dysfunctional telomeres.7 ATM is frequently inactivated in CLL and this confers a poor clinical response.8 Here we examined whether ATM modulates telomere dynamics in CLL B-cells.