Overproduction of BCR‐ABL induces apoptosis in imatinib mesylate‐resistant cell lines

Desplat, Vanessa; Belloc, Françis; Lagarde, Stéphanie; Boyer, S T Catherine; Melo, Junia V.; Reiffers, J.; Perreten, Vincent; Mahon, François‐Xavier

doi:10.1002/cncr.20758

Cited by 13 publications

(14 citation statements)

References 34 publications

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“…This also explains the attenuated cell growth and increased apoptosis rate of KCL22-R after Imatinib withdrawal. Similar results were reported for the cell lines BaF/BCR-ABL and LAMA84 where withdrawal of Imatinib induced apoptosis (34).…”

Section: Discussionsupporting

confidence: 77%

Cytogenetic characterisation and proteomic profiling of the Imatinib-resistant cell line KCL22-R

Rosenhahn¹,

Weise²,

Michel³

et al. 2007

Int J Oncol

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Abstract. Approximately 30% of chronic myeloid leukemia patients show initially no response to Imatinib, a potent inhibitor of BCR-ABL. This intrinsic resistance may be due to BCR-ABL-independent cell growth. Here we analysed the cytogenetic anomalies and the proteomic profiling in KCL22-S and KCL22-R, two Imatinib-sensitive and -resistant derivative cell lines of KCL22. A tetrasomy 8 and a non-reciprocal translocation +der(6)t(6;13)(p11.1;q12) were found only in KCL22-R as new evolved anomalies. Chromosome der(6)t(6;13) showed four variants differing in the chromatin content of 13q14-13qter including the retinoblastoma gene. Due to these sub-clones, approximately 65-79% of the Imatinibtreated KCL22-R cells showed a disomy and 21-35% a monosomy for 13q14. Imatinib removal reduced the main clone to approximately 20% in the benefit of the monosomic sub-clones. This was accompanied by an increased apoptosis rate and was revertible by Imatinib re-treatment. This effect may be connected with genes located in 13q14-qter. Proteomic profiling of the cell lines performed with ProteinChip technology (SELDI) revealed several differentially expressed proteins (n=45). In summary, we demonstrate here the complex changes on the cytogenetic and proteomic level which could be caused by Imatinib and the resistance resulting from it.

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Section: Discussionsupporting

confidence: 77%

Cytogenetic characterisation and proteomic profiling of the Imatinib-resistant cell line KCL22-R

Rosenhahn¹,

Weise²,

Michel³

et al. 2007

Int J Oncol

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“…We found that the removal of dasatinib induces apoptosis after 6 hours. It has been reported that the removal of imatinib leads to the apoptosis of BCR/ABL-overexpressing leukemic cells via a transient activation of the STAT5/Bcl-xL pathway (34). In this study, the BCR/ABL protein was reduced in dasatinib-resistant cells, suggesting that another mechanism was involved in the apoptotic process.…”

Section: Discussionmentioning

confidence: 50%

Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells

Okabe

Tauchi

Ohyashiki

2008

Clinical Cancer Research

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Purpose: Although dual src-family kinase/BCR/ABL inhibitor, dasatinib (BMS-354825),provides therapeutic advantages to imatinib-resistant cells, the mechanism of dasatinib resistance was not fully known. Experimental Design: We used TF-1BCR/ABL cells, by introducing the BCR/ABL gene into a leukemia cell line,TF-1and K562, and established dasatinib-(BMS-R) and imatinib-resistant (IM-R) cells.We characterized chronic myelogenous leukemia drug-resistant cells and examined intracellular signaling.Amol/L (TF-1 BCR/ABL BMS-R), and 25 Amol/L (K562 BMS-R). The number of BCR/ABL copies in resistant cell lines was the same as the parental cell line by fluorescence in situ hybridization analysis. There was no mutation in Abl kinase. We found that protein levels of BCR/ABL were reduced in dasatinib-resistant cell lines. BCR/ABL protein was increased by treatment of an ubiquitin inhibitor. The Src kinase, Lck, as well as mitogen-activated protein kinase and Akt were activated, but p21 WAF , phosphatase and tensin homologue was reduced in K562 BMS-R cells. Removal of dasatinib from the culture medium of K562 BMS-R cells led to apoptosis, and activated caspase 3 and poly (ADP-ribose) polymerase. Conclusion:These results suggest that the expression and protein activation signatures identified in this study provide insight into the mechanism of resistance to dasatinib and imatinib and may be of therapeutic chronic myelogenous leukemia value clinically.

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“…Furthermore, activation of the PDGF receptor results in apoptosis in cultured vascular smooth muscle cells in a time-and dose-dependent manner, involving decreased levels of Bcl-2 and Bcl-xL mRNA (Okura et al 1998). Overexpression of tyrosine kinases might be associated with a decrease in cell proliferation, as exemplified by upregulation of the Bcr-Abl protein due to amplification of the BCR-ABL gene in human imatinib-resistant cell lines (Desplat et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines

et al. 2012

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Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 (IL-3)-dependent murine cell lines like Ba/F3, resulting in loss of IL-3 dependence. Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia (AML) cell lines, despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients. We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death, involving Bax/Bcl2 modulation. Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs, shown here using the HL-60 leukemic cell line. Flt3 expression was investigated in two cellular model systems, the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line, and proliferation was reduced in both systems. HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl-2. Furthermore, we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent. Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines.

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Overproduction of BCR‐ABL induces apoptosis in imatinib mesylate‐resistant cell lines

Cited by 13 publications

References 34 publications

Cytogenetic characterisation and proteomic profiling of the Imatinib-resistant cell line KCL22-R

Cytogenetic characterisation and proteomic profiling of the Imatinib-resistant cell line KCL22-R

Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells

Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines

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