Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation

Augereau, Adeline; Roodenbeke, Claire T'Kint de; Simonet, Thomas; Bauwens, Serge; Horard, Béatrice; Callanan, Mary; Leroux, Dominique; Jallades, Laurent; Salles, Gilles; Gilson, Éric; Poncet, Delphine

doi:10.1182/blood-2010-07-295774

Cited by 47 publications

(50 citation statements)

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“…In the present study, the gene dysregulation observed was similar to that detected by Augereau et al (38). According to our hypothesis, the downregulation of ACD/TPP1 occurs prior to the first stage of malignant transformation, i.e.…”

Section: Discussionsupporting

confidence: 74%

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Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

Witkowska

Strzałka‐Mrozik

Owczarek

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Chronic administration of immunosuppressants has been associated with long-term consequences, including a higher risk of neoplasm development. The processes regulating telomere function exert a major influence on human cancer biology. The present study aimed to assess the effect of immunosuppressive therapy on the expression of genes associated with telomere maintenance and protection in patients following renal transplantation. A total of 51 patients that had undergone kidney transplantation and 54 healthy controls were enrolled in the study. The 51 transplant patients received a three-drug immunosuppressive regimen consisting of cyclosporine A, prednisone and mycophenolate mofetil. In stage 1 of the study, the expression profiles of 123 transcripts, which represented 70 genes, were assessed in peripheral mononuclear blood cells using an oligonucleotide microarray technique in 8 transplant recipients and 4 healthy control subjects. Among the analyzed transcripts, the expression levels of 4 differed significantly between the studied groups; however, only the ACD (adrenocortical dysplasia homolog) gene, encoding the telomere-binding protein POT1-interacting protein 1 (TPP1), was sufficiently specific for telomere homeostasis. The expression of ACD was downregulated in transplant recipients (fold change, 2.11; P=0.006). In stage 2 of the study, reverse transcription-quantitative polymerase chain reaction analysis of ACD, DKC1 and hTERT mRNA was conducted for all transplant patients and control subjects. The results confirmed the downregulation of the ACD gene in patients that had received immunosuppressive therapy (P=0.002). The results of the present study indicate that the downregulation of ACD gene transcription, and thus TPP1 protein expression, may enhance the capacity for cell immortalization, despite normal levels of other key telomere maintenance factors, in patients undergoing immunosuppressive therapy. Furthermore, the results indicate that TPP1 has potential for use as an early clinical marker and/or therapeutic target for cancer in patients following organ transplantation.

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Section: Discussionsupporting

confidence: 74%

“…Augereau et al proposed that telomeric deprotection in the early stages of CLL is a consequence of telomere alteration, in addition to telomere shortening. The authors observed the damage that occurred at an early stage of the disease and suggested that it contributed to the early step of malignant transformation (38).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

Witkowska

Strzałka‐Mrozik

Owczarek

et al. 2015

Experimental and Therapeutic Medicine

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show abstract

“…Other genes including TERF1, TERF2, TERF2IP and POT1 were also decreased but did not show statistical significance. They concluded that DNA damage is present in a proportion of early stage CLL patients and that damage is potentially associated with de-regulated shelterin protection of the telomere and this is not associated with telomere shortening (Augereau et al, 2011). In contrast to this view, several laboratories have provided evidence that short telomeres may indeed be important in CLL, including significant telomere shortening and dysfunction in the early stages.…”

Section: Chronic Lymphocytic Leukaemiamentioning

confidence: 84%

“…This study raised the possibility that TL may be shortened in CLL due to dysfunction of the shelterin complex, which may in turn be due to altered expression of the shelterin and other telomere-associated proteins (Poncet et al, 2007). Following this work, Augereau et al (2011) looked at a cohort of untreated stage A CLL patients in the context of telomere-dysfunction-induced foci (TIF) and expression of shelterin and non-shelterin telomeric genes. Firstly they showed that TIF frequency was increased shelterin proteins) gene expression were significantly decreased in these stage A CLL patients that had TIF in comparison to the previously published data from a mixed cohort of CLL patients that showed normal TINF2 expression, but elevated ACD expression compared to controls.…”

Section: Chronic Lymphocytic Leukaemiamentioning

confidence: 99%

Telomere dysfunction and its role in haematological cancer

Jones¹,

Pepper²,

Baird

2012

Br J Haematol

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SummaryObservations in human tumours, as well as mouse models, have indicated that telomere dysfunction may be a key event driving genomic instability and disease progression in many solid tumour types. In this scenario, telomere shortening ultimately results in telomere dysfunction, fusion and genomic instability, creating the large-scale rearrangements that are characteristic of these tumours. It is now becoming apparent that this paradigm may also apply to haematological malignancies; indeed these conditions have provided some of the most convincing evidence of telomere dysfunction in any malignancy. Telomere length has been shown in several malignancies to provide clinically useful prognostic information, implicating telomere dysfunction in disease progression. In these malignancies extreme telomere shortening, telomere dysfunction and fusion have all been documented and correlate with the emergence of increased genomic complexity. Telomeres may therefore represent both a clinically useful prognostic tool and a potential target for therapeutic intervention.

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“…There is growing evidence that TL carries information of clinical importance for cancer patients. In general, malignant cells have shorter telomeres than their normal counterparts and there is an association between short telomeres and acquisition of genetic aberrations, risk of transformation and tumor progression [1][2][3]. Hence, TL as a potential clinical biomarker in cancer has gained considerable interest and its importance in hematological malignancies has been broadly investigated.…”

Section: Introductionmentioning

confidence: 99%

Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

et al. 2013

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Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n 5 265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P < 0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n 5 119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease. Am. J. Hematol. 88:647-651, 2013. V C 2013 Wiley Periodicals, Inc. IntroductionTelomeres are specialized structures at chromosome ends which serve to protect these ends from being recognized as DNA double-strand breaks. In addition, the repetitive telomere sequences serve as a buffer of non-gene coding DNA when the telomere ends shorten due to the "end replication problem." Telomere maintenance and integrity in hematopoietic cells is executed by telomerase adding new telomeric repeats to the ends in collaboration with telomere length regulators, i.e., the shelterins. The net result of these acting forces defines the actual cellular TL which can serve as a biomarker for telomere integrity and dysfunction. There is growing evidence that TL carries information of clinical importance for cancer patients. In general, malignant cells have shorter telomeres than their normal counterparts and there is an association between short telomeres and acquisition of genetic aberrations, risk of transformation and tumor progression [1][2][3]. Hence, TL as a potential clinical biomarker in cancer has gained considerable interest and its importance in hematological malignancies has been broadly investigated.Chronic lymphocytic leukemia (CLL), a heterogeneous disease with a variable outcome, can be subdivided into clinically relevant subgroups based on molecular, cytogenetic, and phenotypic features and a large set of potential prognostic biomarkers have been identified (reviewed in [4][5][6]). The future status of these biomarkers as a basis for clinical decision makings has not yet been fully defined, although the immunoglobulin heavy chain variable (IGHV) gene mutational status and in particular the presence of certain recurrent genomic aberrations (i.e., 11q2, 112, 13q2, 17p2) are commonly applied biomarkers [5][6][7]. Several studies have lately indicated TL as a potential prognostic marker in CLL, whereby short telomeres may predict poor clinical outcome [8][9][10][11][12][13][14][15]. Furthermore, a stro...

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Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation

Abstract: Cells of B-cell chronic lymphocytic leukemia (B-CLL

Cited by 47 publications

References 46 publications

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

Telomere dysfunction and its role in haematological cancer

Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

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