Effect of imatinib on the signal transduction cascade regulating telomerase activity in K562 (BCR-ABL–positive) cells sensitive and resistant to imatinib

Mor-Tzuntz, Rahav; Uziel, Orit; Shpilberg, Ofer; Lahav, Judith; Raanani, Pia; Bakhanashvili, Mary; Rabizadeh, Esther; Zimra, Yael; Lahav, Meir; Granot, Galit

doi:10.1016/j.exphem.2009.10.005

Cited by 20 publications

(16 citation statements)

References 48 publications

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“…Telomere shortening may result from the proliferative effort required to repopulate the BM and sustain adequate hematopoiesis from a reduced stem cell compartment. At least theoretically, a negative effect of treatment (either TKI or other agents) on telomere dynamics may also result in telomere shortening, as imatinib may inhibit telomerase in hematopoietic cell lines (Uziel et al, 2005;Mor-Tzuntz et al, 2010). However, no evidence exists that this process occurs in normal cells; the low level of h-TERT expression in hematopoietic stem cells does not prevent age-related physiological telomere shortening (Zimmermann et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

“…Based on these considerations, we speculated that Ph-negative hematopoiesis emerging after successful CML treatment could have undergone significant telomere shortening due to prolonged coexistence with the tumor clone, the proliferative effort associated with BM repopulation following successful clearance of Ph-positive hematopoiesis, and/or direct pharmacological inhibition of telomere preservation mechanisms due to TKI treatment (Uziel et al, 2005;Mor-Tzuntz et al, 2010). We wished to evaluate the extent of telomere damage in Ph-negative hematopoiesis after successful CML treatment.…”

Section: Introductionmentioning

confidence: 98%

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Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

Lobetti-Bodoni

Ferrero

Genuardi

et al. 2012

Mechanisms of Ageing and Development

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

Lobetti-Bodoni

Ferrero

Genuardi

et al. 2012

Mechanisms of Ageing and Development

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“…31 Besides its targets counted so far, imatinib was also shown to inhibit telomerase activity in both BCR/ABL expressing and non-expressing cells with the currently unknown intermediate agents. 34 Recently, ceramide metabolism was implicated to be related to the imatinib's mechanism of action. 7 In another study, sphingosine kinase-1 was shown as a downstream regulator of imatinib-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Imatinib induces autophagy throughBECLIN‐1andATG5genes in chronic myeloid leukemia cells

2011

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Imatinib is a chemotherapeutic drug used for the treatment of chronic myeloid leukemia (CML). Recent data showed imatinib-induced cell death in various types of cancers. Autophagy is the physiological process in which cellular components are broken down by the lysosomal activation. In this study, we aimed to examine the effects of imatinib on autophagy in addition to apoptosis in CML cells. Results suggested that imatinib induces autophagy in CML cells through inducing over-expression of BECLIN-1 and ATG5 genes with the statistical significance. Our results demonstrated that autophagy might be involved in imatinib-induced cell death.

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“…Several studies have reported that Gleevec can regulate TA [22-25]. However, the mechanism by which Gleevec affects TA in BCR-ABL-expressing cells is unclear.…”

Section: Introductionmentioning

confidence: 99%

“…However, the mechanism by which Gleevec affects TA in BCR-ABL-expressing cells is unclear. Contradicting results were obtained from different studies; some have shown that Gleevec treatment could increase TA and telomere length [26,27], while a more recent study indicated that Gleevec reduced TA in K562, BCR-ABL positive cells [25]. …”

Section: Introductionmentioning

confidence: 99%

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

et al. 2011

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BackgroundThe cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells.MethodsMolecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels.ResultsOur results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec.ConclusionsOur data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.

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Effect of imatinib on the signal transduction cascade regulating telomerase activity in K562 (BCR-ABL–positive) cells sensitive and resistant to imatinib

Cited by 20 publications

References 48 publications

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

Imatinib induces autophagy throughBECLIN‐1andATG5genes in chronic myeloid leukemia cells

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

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