Oncotarget

Research Papers:

Telomere status in chronic lymphocytic leukemia with TP53 disruption

Romain Guièze, Mélanie Pages, Lauren Véronèse, Patricia Combes, Richard Lemal, Mathilde Gay-bellile, Martine Chauvet, Fabrice Kwiatkowski, Bruno Pereira, Philippe Vago, Jacques-Olivier Bay, Olivier Tournilhac and Andreï Tchirkov _

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Oncotarget. 2016; 7:56976-56985. https://doi.org/10.18632/oncotarget.10927

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Abstract

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

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.


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