5-aza-2′-deoxycytidine-mediated c-myc Down-regulation Triggers Telomere-dependent Senescence by Regulating Human Telomerase Reverse Transcriptase in Chronic Myeloid Leukemia

Grandjenette, Cindy; Schnekenburger, Michaël; Karius, Tommy; Ghelfi, Jenny; Gaigneaux, Anthoula; Henry, Estelle; Dicato, Mario; Diederich, Marc

doi:10.1016/j.neo.2014.05.009

Cited by 42 publications

(38 citation statements)

References 55 publications

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“…Recently, 5-aza was shown to decrease telomere length and reduce telomerase activity in chronic leukemia cell lines. 37 This further corroborates our conclusion that 5-aza mimics natural senescence caused by telomere shortening.…”

Section: Discussionsupporting

confidence: 87%

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Gene expression profiling of replicative and induced senescence

2014

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Cellular senescence is a cell cycle arrest accompanied by high expression of cyclin dependent kinase inhibitors which counteract overactive growth signals, which serves as a tumor suppressive mechanism. Senescence can be a result of telomere shortening (natural or replicative senescence) or DNA damage resulting from exogenous stressors (induced senescence). Here, we performed gene expression profiling through RNA-seq of replicative senescence, adriamycin-induced senescence, H 2 O 2 -induced senescence, and 5-aza-2-deoxycytidine-induced senescence in order to profile the pathways controlling various types of senescence. Overall, the pathways common to all 4 types of senescence were related to inflammation and the innate immune system. It was also evident that 5-aza-induced senescence mirrors natural replicative senescence due to telomere shortening. We also examined the prevalence of senescence-associated secretory phenotype (SASP) factors in the RNA-seq data, showing that it is a common characteristic of all 4 types of senescence. In addition, we could discriminate changes in gene expression due to quiescence during cellular senescence from those that were specific to senescence.

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Section: Discussionsupporting

confidence: 87%

“…Cells were treated for 2 hours (MDAH041) or 1.5 hours (087-N, 087-1 and 172) at 37 C, and were then washed with PBS and growth media was replenished. Cells were grown at 37 C for 5 days before harvest for RNA or protein.…”

Section: Methodsmentioning

confidence: 99%

Gene expression profiling of replicative and induced senescence

2014

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“…[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. Moreover, it is currently unclear whether DNMT inhibition affects telomere function in AML cells.…”

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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“…[8] DAC was also able to decrease telomere length, to reduce telomerase activity and to decrease human telomerase reverse transcriptase (hTERT) expression through decreased binding of c-myc to the hTERT promoter. [9] Then, it induces senescence in CML cell lines. In Kantarjian's report, [10] 130 patients with CML were treated with high dose of DAC.…”

Section: Discussionmentioning

confidence: 99%

The third-time chronic myeloid leukemia in lymphoblastic crisis with ABL1 kinase mutation induced by decitabine, dexamethason combined with nilotinib and dasatinib

Wang

Qiao

Zhu

et al. 2016

Journal of Translational Internal Medicine

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Blast crisis (BC) is the major remaining challenge in the management of chronic myeloid leukemia (CML). The prognosis of the BC patient who carries ABL kinase mutation is very poor. One patient, with lymphoid CML-BC third time, was detected with T315A/F359I/M244V compound mutation by direct sequencing after treatment with tyrosine kinase inhibitions three years. The patient was treated with decitabine, dexamethasone, in combination with nilotinib and dasatinib. Then this patient received a complete hematologic response and cytogenetic response after two cycles of treatment.

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5-aza-2′-deoxycytidine-mediated c-myc Down-regulation Triggers Telomere-dependent Senescence by Regulating Human Telomerase Reverse Transcriptase in Chronic Myeloid Leukemia

Cited by 42 publications

References 55 publications

Gene expression profiling of replicative and induced senescence

Gene expression profiling of replicative and induced senescence

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

The third-time chronic myeloid leukemia in lymphoblastic crisis with ABL1 kinase mutation induced by decitabine, dexamethason combined with nilotinib and dasatinib

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