A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation

Pendino, Frédéric; Sahraoui, T.; Lanotte, Michel; Ségal-Bendirdjian, Évelyne

doi:10.1038/sj.leu.2402470

Cited by 30 publications

(41 citation statements)

References 31 publications

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“…This retrovirally infected NB4-LR1/hTERT-GFP subline has already been described (Pendino et al, 2001(Pendino et al, , 2002 NB4-LR1 and NB4-LR1/GFP cells treated with either ATRA or RARa and RXR agonist combination demonstrated a period of reduced growth (Figure 4a) and after 18 days underwent massive cell death (Figure 4b) due to shortening of the telomere length (Figure 4c). In contrast, NB4-LRl/hTERT-GFP cells continued to proliferate without any significant shortening of telomere length.…”

Section: Combination Of Rara and Rxr-specific Agonists Induces Telomementioning

confidence: 99%

“…Pertinently, the new ATRA-selected variant NB4-LR1 SFD , previously isolated for its resistance to the death induction by long-term ATRA treatment, because of its defective pathway for ATRA long-term downregulation of telomerase activity (Pendino et al, 2002), was also resistant to the agonists combination (Figure 4). …”

Section: Combination Of Rara and Rxr-specific Agonists Induces Telomementioning

confidence: 99%

“…In the present paper, dose-response investigations demonstrate that (1) growth arrest and cell death can be achieved only when more than 60% of telomerase inhibition is reached, (2) such an inhibition requires a pharmacological concentration of ATRA (0.5-1 mM). Therefore, despite this high in vitro efficacy of ATRA to downregulate telomerase (Pendino et al, 2001(Pendino et al, , 2002, any validation of an ATRA-based antitelomerase therapy using this high concentration of ATRA can be questioned. Furthermore, the long-term ATRA use at pharmacological concentration is hampered by undesirable systemic side effects, including RA syndrome and selection of ATRA-resistant tumor cells.…”

Section: Atra-based Differentiation Therapy Leads To Complete Remissimentioning

confidence: 99%

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Retinoic acid receptor α and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death

et al. 2003

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Section: Combination Of Rara and Rxr-specific Agonists Induces Telomementioning

confidence: 99%

Section: Combination Of Rara and Rxr-specific Agonists Induces Telomementioning

confidence: 99%

Section: Atra-based Differentiation Therapy Leads To Complete Remissimentioning

confidence: 99%

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Retinoic acid receptor α and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death

et al. 2003

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“…The maturation-resistant human APL cell lines, NB4-LR1 and the selected subline NB4-LR1 SFD , were cultured as previously described. [37][38][39][40] All cells were incubated at 37 1C at 5% CO 2 atmosphere (Binder Incubators, Nanterre, France). For treatment, cells were seeded at a density of 1-2 Â 10 5 cells/ml in medium supplemented with ATRA (1 mM).…”

Section: Chemicals and Cell Culturementioning

confidence: 99%

“…Importantly, we reported the isolation of a variant of NB4-R1 cells (NB4-R1 SFD ), which bypasses this death step, because of a reactivated telomerase, despite the continuous presence of ATRA. 37 It is noteworthy that the reactivation of telomerase after an initial step of downregulation resembles what is observed during tumorigenesis when telomerase is reactivated; therefore, this cell line could serve as a unique cell model to study the molecular events occurring during the oncogenic reactivation of telomerase.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

Azouz

Hillion

et al. 2010

Leukemia

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The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1 SFD ), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1 SFD cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1 SFD cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation.

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Complex context relationships between DNA methylation and accessibility, histone marks, and hTERT gene expression in acute promyelocytic leukemia cells: perspectives for all‐trans retinoic acid in cancer therapy

et al. 2020

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Telomerase (hTERT) reactivation and sustained expression is a key event in the process of cellular transformation. Therefore, the identification of the mechanisms regulating hTERT expression is of great interest for the development of new anticancer therapies. Although the epigenetic state of hTERT gene promoter is important, we still lack a clear understanding of the mechanisms by which epigenetic changes affect hTERT expression. Retinoids are well-known inducers of granulocytic maturation in acute promyelocytic leukemia (APL). We have previously shown that retinoids repressed hTERT expression in the absence of maturation leading to growth arrest and cell death. Exploring the mechanisms of this repression, we showed that transcription factor binding was dependent on the epigenetic status of hTERT promoter. In the present study, we used APL cells lines and publicly available datasets from APL patients to further investigate the integrated epigenetic events that promote hTERT promoter transition from its silent to its active state, and inversely. We showed, in APL patients, that the methylation of the distal domain of hTERT core promoter was altered and correlated with the outcome of the disease. Further studies combining complementary approaches carried out on APL cell lines highlighted the significance of a domain outside the minimal promoter, localized around 5 kb upstream from the transcription start site, in activating hTERT. This domain is characterized by DNA hypomethylation and H3K4Me3 deposition. Our findings suggest a cooperative interplay between hTERT promoter methylation, chromatin accessibility, and histone modifications that force the revisiting of previously proposed concepts regarding hTERT epigenetic regulation. They represent, therefore, a major advance in predicting sensitivity to retinoid-induced hTERT repression and, more Abbreviations APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; BAC, bacterial artificial chromosome; FISH, fluorescence in situ hybridization; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; hTERT, human telomerase reverse transcriptase; hTR, human telomerase RNA; NOMe-seq, nucleosome occupancy and methylome sequencing; qRT-PCR, quantitative reverse transcriptase polymerase chain reaction; RRBS, reduced representation bisulfite sequencing; SAM, S-adenosylmethionine; SNP, single nucleotide polymorphism; SSC, saline sodium citrate; TPE-OLD, telomere position effect over long distances; TSS, transcription start site.

show abstract

A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation

Cited by 30 publications

References 31 publications

Retinoic acid receptor α and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death

Retinoic acid receptor α and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

Complex context relationships between DNA methylation and accessibility, histone marks, and hTERT gene expression in acute promyelocytic leukemia cells: perspectives for all‐trans retinoic acid in cancer therapy

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