Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X‐irradiation and glucocorticoids

Amos, Tim; Lewis, J. L.; Grand, F. H.; Gooding, Roger; Goldman, John M.; Gordon, M. Y.

doi:10.1111/j.1365-2141.1995.tb05308.x

Cited by 77 publications

(50 citation statements)

References 30 publications

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“…Similarly, Bedi and colleagues (1994) showed that hematopoietic progenitors from CML patients are relatively resistant to induction of apoptosis, and that antisense treatment can sensitize these cells. This resistance to apoptosis of hematopoietic progenitors from CML patients is, however, controversial (Amos et al, 1995). More recently, Bedi and colleagues (1995) have suggested that the anti-apoptotic effect of Bcr-Abl is related to a delayed progression through G2/M, allowing time for DNA repair and prevention of mitotic catastrophe.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Bcr-Abl in K562 cells restores susceptibility to apoptosis: Characterization of the apoptotic death

et al. 1997

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We examined the susceptibility of a variety of human leukemic cell lines to the induction of apoptosis. K562, a chronic myelogenous leukemic cell line which expresses the bcr-abl fusion gene, was found to be extremely resistant to apoptosis, irrespective of the inducing agent. This resistance can be attributed to the deregulated Abl kinase activity of bcr-abl, as downregulation of its expression using antisense oligodeoxynucleotides targeted to the beginning of the abl sequence in this chimeric gene rendered these cells susceptible to cytotoxic drug-induced apoptosis. Examination of the morphological and biochemical features of apoptosis in K562 cells revealed the typical membrane blebbing and chromatin condensation associated with this form of cell death. In situ TdT-mediated end labeling of the DNA revealed the presence of strand breaks in the treated cells and field inversion gel electrophoresis revealed the presence of large 10 ± 50 kb fragments. However there was an absence of oligonucleosomal DNA fragmentation, whether or not Bcr-Abl was expressed. Thus, while inhibition of expression of Bcr-Abl renders K562 cells susceptible to apoptosis, the absence of oligonucleosomal DNA fragmentation in these cells is independent of the function of this molecule.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Bcr-Abl in K562 cells restores susceptibility to apoptosis: Characterization of the apoptotic death

et al. 1997

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“…33 The heterogeneity of patient samples and the potential differences of BCR-ABL protein expression, which varies from one patient (and probably from one hematopoietic cell) to another, could explain discordant findings obtained with regard to the inhibition of apoptosis in primary patient samples. 9,10 Our model distinctly shows that: (1) BCR-ABL protein expression in a human hematopoietic cell line is not sufficient to induce growth factor independence; and (2) the anti-apoptotic effect of BCR-ABL is fully operational only when BCR-ABL is expressed at high levels. Our data confirm, therefore, for the first time in pluripotent human cells, the results obtained by Pierce et al 34 in the murine FDCP-mix cell line in which the tyrosine kinase activity of BCR-ABL was found to be compatible with growth factor dependence and differentiation ability.…”

Section: Figurementioning

confidence: 99%

“…[1][2][3] It has been established that BCR-ABL triggers a variety of molecular events inside the target cell with activation of several molecular pathways such as RAS, PI-3K and CRK-L. 4 evance with regard to human CML in which there have been conflicting reports with regard to the anti-apoptotic effects of BCR-ABL. [7][8][9][10] Similarly, although BCR-ABL gene transfer induces growth factor independence in growth factor-dependent cell lines, human hematopoietic progenitors bearing the BCR-ABL translocation as assessed by PCR or FISH analyses are not growth factor-independent and present only subtle abnormalities such as Epo-independent erythroid colony growth 11 in the presence of Steel factor. 12 Anti-apoptotic activities of BCR-ABL have been shown to be reverted by inhibition of the tyrosine kinase activity of BCR-ABL.…”

Section: Introductionmentioning

confidence: 99%

Biological effects induced by variable levels of BCR-ABL protein in the pluripotent hematopoietic cell line UT-7

et al. 2000

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There is currently no satisfactory model allowing analysis of dose-effect relationships of BCR-ABL proteins in human hematopoietic cells. To study comparatively the proliferative, differentiative and anti-apoptotic actions of different levels of BCR-ABL proteins in the context of the same cellular background, we have introduced the BCR-ABL gene into the GM-CSF-dependent pluripotent human cell line UT-7. Individual clones expressing BCR-ABL were analyzed by Western blots. After normalization to equivalent levels of endogenous ABL protein, 14 clones always grown in GM-CSF were found to express low but variable levels of BCR-ABL whereas two clones selected in the absence of GM-CSF expressed very high levels of BCR-ABL. All low-level BCR-ABL expressing clones exhibited a behavior similar to that of the GM-CSF-dependent parental cells as they ceased to proliferate upon growth factor deprivation and showed a strong proliferative response upon GM-CSF addition. One out of 14 clones showed progressive GM-CSF independence during culture over several weeks and was found to have a significant increase of BCR-ABL expression at that time. The resistance of this clone (E8-2) to different apoptotic stimuli was found to be increased as compared to its low BCR-ABL-expressing counterpart (E8-1) and similar to that observed in clones with very high levels of BCR-ABL (UT-7/9 and UT-7/11) which were totally resistant to apoptotic stimuli. When injected into nude mice, parental UT-7 cells and clones with low-level of BCR-ABL were not tumorigenic over 10 weeks of observation whereas UT-7 clones with high levels of BCR-ABL (UT-7/9, UT-7/11 and UT-7/E8-2) induced aggressive tumors in 2-4 weeks with a significant correlation between the amount of BCR-ABL protein and the rate of tumor growth. In conclusion, the establishment of an in vitro and in vivo CML model using UT-7 cells suggests for the first time in human cells, that the fully transformed phenotype induced by BCR-ABL requires high levels of BCR-ABL expression. These findings suggest that variable levels of BCR-ABL in primary patient cells could also be responsible for the different phenotypic features seen in chronic and acute phases of CML, such as the differentiation ability induced by growth factors. Leukemia (2000) 14, 662-670.

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“…62,63,73 Most but not all studies using p210 BCR/ABL expressing cell lines have demonstrated that BCR-ABL expression protects from apoptosis induced by physical and chemical stresses. [74][75][76][77][78] Additionally, chronic phase CML CD34 + cells undergo delayed apoptotic death upon cytokine withdrawal when compared with normal progenitors. [79][80][81] The use of antisense oligonucleotides against BCR-ABL could reverse the delay in apoptosis in CML cell lines.…”

Section: Decreased Apoptosismentioning

confidence: 99%

Chronic myelogenous leukemia: mechanisms underlying disease progression

2002

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Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABLmediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.

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Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X‐irradiation and glucocorticoids

Cited by 77 publications

References 30 publications

Downregulation of Bcr-Abl in K562 cells restores susceptibility to apoptosis: Characterization of the apoptotic death

Downregulation of Bcr-Abl in K562 cells restores susceptibility to apoptosis: Characterization of the apoptotic death

Biological effects induced by variable levels of BCR-ABL protein in the pluripotent hematopoietic cell line UT-7

Chronic myelogenous leukemia: mechanisms underlying disease progression

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