Telomere status in chronic lymphocytic leukemia with TP53 disruption
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Romain Guièze1,2, Mélanie Pages3,4, Lauren Véronèse5,6,7, Patricia Combes5,6,7, Richard Lemal1,2, Mathilde Gay-bellile5,6,7, Martine Chauvet8,9, Mary Callanan8,9, Fabrice Kwiatkowski7,10, Bruno Pereira11, Philippe Vago5,6,7, Jacques-Olivier Bay1,2, Olivier Tournilhac1,2, Andreï Tchirkov5,6,7
1CHU Clermont-Ferrand, Hématologie Clinique, Clermont-Ferrand, France
2EA 7283 CREaT, Université d’Auvergne, Clermont-Ferrand, France
3Department de Neuropathologie, Hôpital Sainte-Anne, Paris, France
4Université Paris Descartes, Paris, France
5Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France
6CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France
7EA 4677 ERTICa, Université d’Auvergne, Clermont-Ferrand, France
8Inserm U823, Institut Albert Bonniot & Université Joseph Fourier, Grenoble, France
9CHU Grenoble, Laboratoire de Génétique Onco-hématologique, Grenoble, France
10Centre Jean Perrin, Clermont-Ferrand, France
11Direction de la Recherche Clinique et de l’Innovation, Département de Biostatistiques, CHU Clermont-Ferrand, Clermont-Ferrand, France
Andreï Tchirkov, email: [email protected]
Keywords: chronic lymphocytic leukemia, TP53, telomere, hTERT, shelterin
Received: April 13, 2016 Accepted: July 10, 2016 Published: July 29, 2016
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.
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