hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia—associations with immunophenotype and cytogenetic subgroup

Borssén, Magnus; Cullman, Inger; Norén‐Nyström, Ulrika; Sundström, Christer; Porwit, Anna; Forestier, Erik; Roos, Göran

doi:10.1016/j.exphem.2011.08.014

Cited by 25 publications

(22 citation statements)

References 34 publications

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“…Consistent with this, TL in ALL is shorter than in AML at the time of diagnosis, though TL at time of relapse is shorter in AML than ALL (Capraro et al, 2011) and TL in ALL has been reported to be longer after treatment (Borssen et al, 2011). TL at diagnosis is shorter in B-ALL in comparison to T-ALL.…”

Section: Acute Leukaemiassupporting

confidence: 67%

“…In contrast to AML, TA is lower in ALL (Capraro et al, 2011), this probably arises as a consequence of TERT promoter methylation (Borssen et al, 2011). Consistent with this, TL in ALL is shorter than in AML at the time of diagnosis, though TL at time of relapse is shorter in AML than ALL (Capraro et al, 2011) and TL in ALL has been reported to be longer after treatment (Borssen et al, 2011).…”

Section: Acute Leukaemiassupporting

confidence: 58%

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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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Section: Acute Leukaemiassupporting

confidence: 67%

Section: Acute Leukaemiassupporting

confidence: 58%

Telomere dysfunction and its role in haematological cancer

Jones¹,

Pepper²,

Baird

2012

Br J Haematol

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“…However, the TERT promoter is very unique: widespread DNA demethylation of the promoter occurs in human fibroblasts and other normal cells where the TERT transcription is stringently repressed, whereas the hyper-methylation of the specific TERT promoter region is required for the gene activation in many kinds of malignant cells. [25–30] Therefore, the effect of DNMTIs on TERT expression is dependent on cell type and context. Our present results show that 5-AZA treatment led to down-regulation of TERT expression coupled with diminished telomerase activity in KG1A and HEL cells, indicating the methylation-dependent TERT regulation in AML cells.…”

Section: Discussionmentioning

confidence: 99%

“…[11] Unlike other gene promoters where their methylation silences gene transcription or expression, the methylated TERT promoter at certain sites is associated with the gene de-repression and telomerase activation in malignant cells. [11, 25–30] Published data have revealed that the effect of DNMTIs on TERT expression in malignant cells varies dependent on cell types. [25, 31–36] Importantly, as TERT is involved in chemo- and radio-resistance of malignant cells, [22–24] it is critical to elucidate whether TERT is capable of protecting DNMTI-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression

Zhang

Jonge

et al. 2015

Oncotarget

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DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity.

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“…23 Hypermethylation of MLH1 has been reported in colorectal cancer, 24 gastric cancer, 25 ovarian cancer 26 and others. Hypermethylation of hTERT was reported in acute lymphoblastic leukaemia, 27 hepatic cancer, 28 non-small cell lung cancer 29 and others. Hypermethylation of TP53 has been reported in acute lymphoblastic leukaemia, 30 while hypomethylation was reported in acute non-lymphocytic leukaemia.…”

Section: Introductionmentioning

confidence: 98%