Chromatin nucleoprotein complexes containing tightly bound c-abl, p53 and bcl-2 gene sequences: correlation with progression of chronic myelogenous leukemia

Nicolson, Nancy L.; Talpaz, Moshe; Nicolson, Garth L.

doi:10.1016/0378-1119(96)88650-1

Cited by 7 publications

(5 citation statements)

References 12 publications

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“…It is the first oncogene found to function through production of an inhibitor of programmed cell death [19] . Overexpression of Bcl-2 is common in many human cancers, and contributes to increased resistance to chemotherapy [20][21][22] . Bcl-2 antisense oligonucleotides can increase the anticancer drug sensitivity of tumor cells [23,24] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bcl-2 expression by a novel tumor-specific RNA interference system increases chemosensitivity to 5-fluorouracil in Hela cells

Huang

et al. 2006

Acta Pharmacologica Sinica

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Aim: RNA interference (RNAi) has been proposed as a potential treatment for cancer, but the lack of cellular targets limits its use in cancer gene therapy. No current technology has achieved direct tumor‐specific gene silencing using RNAi. In the present study we attempt to develop a tumor‐specific RNAi system using the human telomerase reverse transcriptase (hTERT) promoter; furthermore, we analyzed its inhibitive effect on Bcl‐2 expression. Methods: The vectors containing a small hairpin RNA (shRNA) to target exogenous reporters [firefly luciferase and enhanced green fluorescent protein (EGFP)] and endogenous gene (Bcl‐2) were constructed. Luciferase expression was determined by dual luciferase assay. Reverse transcription‐polymerase chain reaction (RT‐PCR), fluorescence microscopy and fluorescence‐activated cell sorting (FACS) were used to measure EGFP expression. Inhibition of Bcl‐2 was evaluated by RT‐PCR and Western blotting. Cell proliferation and viability were measured by using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay. FACS was used to analyze the cell cycle distribution profile. Results: We showed that with the hTERT promoter directly driving shRNA transcription, expression of the exogenous reporters (LUC and EGFP) in tumor cells, but not normal cells, was specifically inhibited in vitro. The hTERT promoter‐driven shRNA also depressed the expression of Bcl‐2. Inhibition of Bcl‐2 did not affect cell proliferation, but increased the chemosensitivity of HeLa cells to 5‐fluorouracil. Conclusion: The present study describes an efficient RNAi system for gene silencing that is specific to tumor cells using the hTERT promoter. Suppression of Bcl‐2 by using this system sensitized HeLa cells to 5–fluorouracil. This system may be useful for RNAi therapy.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Bcl-2 expression by a novel tumor-specific RNA interference system increases chemosensitivity to 5-fluorouracil in Hela cells

Huang

et al. 2006

Acta Pharmacologica Sinica

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“…The tumor suppressor P53 that functions to initiate cell cycle arrest and apoptotic pathways in cells has been found to be upregulated in response to IFN- α [ 9 , 28 ]. P210 bcr/abl is characterized as the specific biomarker of CML and its expression level symbolizes the progression of CML [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Effects of a Particular Heptapeptide on the IFN-α-Sensitive CML Cells

Yang

Chen

Wan

et al. 2015

BioMed Research International

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Using the phage display biopanning technique, we have previously identified a heptapeptide KLWVIPQ which specifically binds to the surface of the IFN-α-sensitive but not the IFN-α-resistant CML cells. The effects of this heptapeptide on the IFN-α-sensitive CML cells were investigated in the present study. IFN-α-sensitive KT-1/A3 and IFN-α-resistant KT-1/A3R CML cells were transfected by pEGFP-KLWVIPQ expression vector and/or induced by IFN-α. WST-1 cell proliferation assay, flow cytometry, and western blotting were performed to determine the effects of this heptapeptide and/or IFN-α on CML cells. The viability of the KT-1/A3 cells was inhibited and apoptosis was induced by either expression of the heptapeptide KLWVIPQ or IFN-α treatment with concurrent upregulation of P53 and downregulation of P210bcr/abl. However, these effects were not observed in the IFN-α-resistant KT-1/A3R cells. These results suggest that the heptapeptide KLWVIPQ shares a similar mechanism with IFN-α in the regulation of CML cell growth and apoptosis, implying that the heptapeptide KLWVIPQ could be a novel target to go further into mechanisms of IFN-α sensitivity and/or resistance in CML.

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“…[25][26][27][28] In addition, clinical findings suggest that progression of CML from chronic to advanced phase is associated with BCR-ABL induced nuclear localization of BCL-XL where, along with c-ABL and p53, it binds chromatin nucleoprotein complexes (CNC), thus presumably inducing altered genetic activity of the cell. 29 Within the first 30 min of dasatinib exposure there is a rapid and dramatic shift from nuclear to cytoplasmic expression of BCL-XL protein. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is difficult to determine from imaging alone whether this reflects an overall decrease in BCL-XL transcription and expression, but it does correlate with reports of decreased BCL-XL expression levels detected in patients receiving TKI therapy compared to that found prior to treatment. 26 The early effects of dasatinib upon BCL-XL localization thus may, in part, explain its cytotoxic effect in sensitive CML cells, [25][26][27][28][29][30][31] but may also have cytostatic effects in cells not undergoing apoptosis upon shuttling of BCL-XL from the nucleus. 2…”

Section: Resultsmentioning

confidence: 99%

Intracellular protein trafficking kinetics in chronic myeloid leukemia stem cells using a microfluidic platform

Faley

Copland²,

Reboud

et al. 2012

Integr. Biol.

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The oncogenic fusion protein BCR-ABL is produced by chronic myeloid leukemia (CML) cells and functions as an abnormal, constitutively active tyrosine kinase that interferes with normal migratory and apoptotic behaviour of cells. Small molecule tyrosine kinase inhibitors (TKIs), such as dasatinib, eliminate CML progenitor cells, but fail to target the stem cell fraction resulting in persistent disease. In order to achieve a cure for CML in the majority of patients, we need an improved understanding of intracellular signalling dynamics, including the shuttling of BCR-ABL between cytosolic and nuclear compartments. In the past, the instability of BCR-ABL in assays using conventional immunohistochemical techniques has made this difficult and has not allowed for reliable analysis at the single cell level. Here we show how the utilization of rapid on-chip cell fixation within a microfluidic platform provides a means to immunofluorescently analyze the spatiotemporal localization of both BCR-ABL and c-ABL, as well as the linked apoptosis mediator, BCL-XL, in arrays of single CD34+ CML stem/progenitor cells, without cell loss. We demonstrate this proceeds up to 4 times faster than benchtop methods. Our results indicate that whilst both BCR-ABL and c-ABL shuttle from the cytoplasm to the nucleus following dasatinib treatment, the temporal dynamics are not synchronized. The microfluidic platform has the potential to provide insights into the intracellular signalling events in single cells. The ability to examine signalling events and assess BCR-ABL expression/activity in isolated cells in "real-time" may help elucidate the characteristics of rare CML stem cell events, which lead to the resistance of CML stem cells to TKIs.

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Chromatin nucleoprotein complexes containing tightly bound c-abl, p53 and bcl-2 gene sequences: correlation with progression of chronic myelogenous leukemia

Cited by 7 publications

References 12 publications

Inhibition of Bcl-2 expression by a novel tumor-specific RNA interference system increases chemosensitivity to 5-fluorouracil in Hela cells

Inhibition of Bcl-2 expression by a novel tumor-specific RNA interference system increases chemosensitivity to 5-fluorouracil in Hela cells

Effects of a Particular Heptapeptide on the IFN-α-Sensitive CML Cells

Intracellular protein trafficking kinetics in chronic myeloid leukemia stem cells using a microfluidic platform

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