Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

Lin, T; Norris, Kevin; Heppel, Nicole H.; Pratt, Guy; Allan, James M.; Allsup, David; Bailey, James R.; Cawkwell, Lynn; Hills, Robert Kerrin; Grimstead, Julia W.; Jones, Rhiannon E.; Britt-Compton, Bethan; Fegan, Christopher; Baird, Duncan Martin; Pepper, Chris

doi:10.1111/bjh.13023

Cited by 79 publications

(94 citation statements)

References 33 publications

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“…In particular, mutant patient cells contained telomeric STELA products <2.3 kb, which have been correlated with telomere dysfunction and fusion (Lin et al 2014). The finding that telomerase can immortalize the POT1 CP cells and diminishes the presence of the extremely short telomeres argues in favor of the shortened telomeres causing the observed proliferation defect.…”

Section: Discussionmentioning

confidence: 94%

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

et al. 2016

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Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/ primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1 CP ) in two siblings with CP. POT1 CP induced a proliferative arrest that could be bypassed by telomerase. POT1 CP was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1CP was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1CP was also defective in the maintenance of the telomeric C strand, causing extended 3 ′ overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).

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Section: Discussionmentioning

confidence: 94%

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

et al. 2016

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“…We used haplotype analysis to confirm the involvement solely of the shorter MRC5 HPVE6E7 XpYp allele (Baird et al 2003) in these sequenced fusions (Supplemental Fig. 1B), consolidating demonstrations of the length-dependent threshold for telomere fusion to occur (Capper et al 2007;Lin et al 2014). We performed manual curation and sequence verification of all telomere linkages exceeding mapping quality (Li 2014) and BLAST alignment (Altschul et al 1990) score thresholds defined using training data sets (described in the Supplemental Methods).…”

Section: High Resolution Mapping Of Inter-and Intra-chromosomal Recommentioning

confidence: 88%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 doubleknockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.

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“…Most of our patients (86 %) were studied at an early stage of the disease. Different authors [22,30,31] found evidences of telomeric damage in early stage patients suggesting that short telomeres could be a possible marker for clinical progression. In addition, Ricca et al [11] referred preliminary results indicating that TL is not always stable over time in CLL, and suggesting that TL is influenced by the natural history of the disease.…”

Section: Discussionmentioning

confidence: 99%

Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia

et al. 2015

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Telomeric dysfunction has been proposed as an emerging prognostic factor in chronic lymphocytic leukemia (CLL). We have explored the relationship between telomere length (TL) and chromosome alterations studied by fluorescence in situ hybridization (FISH) and conventional cytogenetics in 107 newly diagnosed CLL patients; 61 normal controls were also evaluated. Results were correlated with clinical parameters and outcome. Absolute TL measurement was carried out on DNA samples by real-time quantitative PCR. A significant telomere shortening in patients compared to controls was observed (p = 0.0001). The analysis taking into account FISH risk groups showed shorter TLs in cases with del11q/17p compared to patients with 13q14 deletion as a single alteration (p = 0.0037), no alterations (NA) (p = 0.028), and cases with abnormal karyotypes (p = 0.014). In addition, a significant TL reduction in cases with two or more anomalies with respect to those with NA (p = 0.033) and with one alteration (p = 0.045), and no differences compared to cases with deletions 11q/17p were observed. Patients with only one anomaly did not show statistical differences with respect to controls; meanwhile, a significant TL reduction in cases with two or more aberrations was observed (p = 0.025). The shortest telomeres were associated to 11q/17p deletion with significant differences compared to the remaining groups (p ≤ 0.045). Significantly shorter treatment free survival in patients with two or more alterations compared to those with NA plus one abnormality was observed (p = 0.0006). Our findings support the association between short TL and chromosome alterations in CLL and indicate the importance of telomere dysfunction in driving genomic instability in this pathology.

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Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

Cited by 79 publications

References 33 publications

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia

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