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Abstract
In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.
Highlights
Telomeres protect chromosomal ends and are comprised of tracts of G-rich nucleotide repeats bound by a protein complex, shelterin, containing TRF1 and TRF2, POT1, TIN2 (TRF1-interacting protein 2), TPP1 (POT1–TIN2 organizing protein, www.impactjournals.com/oncotarget known as ACD) and RAP1 [1, 2].The protective function of telomeres requires a sufficient amount of telomeric repeats and integrity of the shelterin complex
We investigated the impact of TP53 status on telomeres in relation to other adverse biological features of chronic lymphocytic leukemia (CLL), which are known to correlate with telomere length and hTERT expression [14, 19]
All these characteristics increased the risk of having short telomere length and high hTERT expression, TP53 disruption had the strongest impact in the multiple logistic regression analyses (Figure 1C)
Summary
Telomeres protect chromosomal ends and are comprised of tracts of G-rich nucleotide repeats bound by a protein complex, shelterin, containing TRF1 and TRF2 (telomeric repeat binding factors 1 and 2), POT1 (protection of telomeres 1), TIN2 (TRF1-interacting protein 2), TPP1 (POT1–TIN2 organizing protein, www.impactjournals.com/oncotarget known as ACD) and RAP1 (repressor-activator protein 1) [1, 2].The protective function of telomeres requires a sufficient amount of telomeric repeats and integrity of the shelterin complex. Cells with dysfunctional telomeres are removed via senescence or apoptosis, and the p53 protein, a guardian of genomic integrity, regulates this physiological response. P53 deficiency and hTERT activation cooperate in oncogenesis, promoting genetically unstable and immortal tumor cell clones [3,4,5]. Telomere shortening and hTERT expression have been related to poor outcomes [6,7,8,9,10]. The shelterin complex is globally dysregulated at the transcriptional level [11, 12] and the presence of dysfunctional telomeres has been correlated with a downregulation of shelterin genes [11, 13], but the relationship between shelterin status and the clinico-biological parameters and outcomes of CLL remain unknown
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