title: Telomere status in chronic lymphocytic leukemia with TP53 disruption.
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.
authors.affiliation: CHU Clermont-Ferrand, Hématologie Clinique, Clermont-Ferrand, France.|EA 7283 CREaT, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guièze
authors.affiliation: Department de Neuropathologie, Hôpital Sainte-Anne, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pages
authors.affiliation: Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France.|CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France.|EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Lauren
authors.initials: L
authors.lastname: Véronèse
authors.affiliation: Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France.|CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France.|EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Combes
authors.affiliation: CHU Clermont-Ferrand, Hématologie Clinique, Clermont-Ferrand, France.|EA 7283 CREaT, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Lemal
authors.affiliation: Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France.|CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France.|EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Gay-Bellile
authors.affiliation: Inserm U823, Institut Albert Bonniot & Université Joseph Fourier, Grenoble, France|CHU Grenoble, Laboratoire de Génétique Onco-hématologique, Grenoble, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Chauvet
authors.affiliation: Inserm U823, Institut Albert Bonniot & Université Joseph Fourier, Grenoble, France|CHU Grenoble, Laboratoire de Génétique Onco-hématologique, Grenoble, France.
authors.forename: Mary
authors.initials: M
authors.lastname: Callanan
authors.affiliation: EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France.|Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Kwiatkowski
authors.affiliation: Direction de la Recherche Clinique et de l'Innovation, Département de Biostatistiques, CHU Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pereira
authors.affiliation: Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France.|CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France.|EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vago
authors.affiliation: CHU Clermont-Ferrand, Hématologie Clinique, Clermont-Ferrand, France.|EA 7283 CREaT, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Bay
authors.affiliation: CHU Clermont-Ferrand, Hématologie Clinique, Clermont-Ferrand, France.|EA 7283 CREaT, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Tournilhac
authors.affiliation: Université Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, France.|CHU Clermont-Ferrand, Cytogénétique Médicale, Clermont-Ferrand, France.|EA 4677 ERTICa, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Andreï
authors.initials: A
authors.lastname: Tchirkov
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000378:metabolism; D014408:Biomarkers, Tumor; D004252:DNA Mutational Analysis; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D057057:Serine Proteases / Q000378:metabolism; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000648:ultrastructure*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495876:ACD protein, human; D014408:Biomarkers, Tumor; C440849:POT1 protein, human; D000089804:Shelterin Complex; C440868:TINF2 protein, human; C495901:TP53 protein, human; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
keywords: TP53; chronic lymphocytic leukemia; hTERT; shelterin; telomere