Telomere status in chronic lymphocytic leukemia with TP53 disruption.
Fiche publication
Date publication
août 2016
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CALLANAN Mary
Tous les auteurs :
Guièze R, Pages M, Véronèse L, Combes P, Lemal R, Gay-Bellile M, Chauvet M, Callanan M, Kwiatkowski F, Pereira B, Vago P, Bay JO, Tournilhac O, Tchirkov A
Lien Pubmed
Résumé
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.
Mots clés
TP53, chronic lymphocytic leukemia, hTERT, shelterin, telomere
Référence
Oncotarget. 2016 08 30;7(35):56976-56985