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Telomere status in chronic lymphocytic leukemia with TP53 disruption

2016; Impact Journals LLC; Volume: 7; Issue: 35 Linguagem: Inglês

10.18632/oncotarget.10927

1949-2553

Romain Guièze, Mélanie Pagès, Lauren Véronèse, Patricia Combes, Richard Lemal, Mathilde Gay‐Bellile, Martine Chauvet, Mary Callanan, Fabrice Kwiatkowski, Bruno Pereira, Philippe Vago, Jacques‐Olivier Bay, Olivier Tournilhac, Andréï Tchirkov,

Cancer-related Molecular Pathways

// Romain Guièze 1, 2 , Mélanie Pages 3, 4 , Lauren Véronèse 5, 6, 7 , Patricia Combes 5, 6, 7 , Richard Lemal 1, 2 , Mathilde Gay-bellile 5, 6, 7 , Martine Chauvet 8, 9 , Mary Callanan 8, 9 , Fabrice Kwiatkowski 7, 10 , Bruno Pereira 11 , Philippe Vago 5, 6, 7 , Jacques-Olivier Bay 1, 2 , Olivier Tournilhac 1, 2 , Andreï Tchirkov 5, 6, 7 1 CHU Clermont-Ferrand, Hématologie Clinique, Clermont-Ferrand, France 2 EA 7283 CREaT, Université d'Auvergne, Clermont-Ferrand, France 3 Department de Neuropathologie, Hôpital Sainte-Anne, Paris, France 4 Université Paris Descartes, Paris, France 5 Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France 6 CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France 7 EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France 8 Inserm U823, Institut Albert Bonniot & Université Joseph Fourier, Grenoble, France 9 CHU Grenoble, Laboratoire de Génétique Onco-hématologique, Grenoble, France 10 Centre Jean Perrin, Clermont-Ferrand, France 11 Direction de la Recherche Clinique et de l'Innovation, Département de Biostatistiques, CHU Clermont-Ferrand, Clermont-Ferrand, France Correspondence to: Andreï Tchirkov, email: atchirkov@chu-clermontferrand.fr Keywords: chronic lymphocytic leukemia, TP53 , telomere, hTERT , shelterin Received: April 13, 2016 Accepted: July 10, 2016 Published: July 29, 2016 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.