Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR–ABL tyrosine kinase

@article{Vigneri2001InductionOA,
  title={Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR–ABL tyrosine kinase},
  author={Paolo Vigneri and Jean Y. J. Wang},
  journal={Nature Medicine},
  year={2001},
  volume={7},
  pages={228-234}
}
The chimeric BCR–ABL oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). BCR–ABL contains nuclear import and export signals but it is localized only in the cytoplasm where it activates mitogenic and anti-apoptotic pathways. We have found that inhibition of the BCR–ABL tyrosine kinase, either by mutation or by the drug STI571, can stimulate its nuclear entry. By combining STI571 with leptomycin B (LMB) to block nuclear export, we trapped BCR–ABL in the nucleus and the… 
Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus
TLDR
It is shown that a rapalog nuclear transport system (RNTS) containing six nuclear localization signals directs Bcr-Abl into the nucleus and that nuclear entrapped Bcr -Abl induces apoptosis and inhibits proliferation of CML cells by activating p73 and shutting down cytoplasmic oncogenic signals mediated by Bcr,Abl.
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TLDR
Results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients.
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This study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance by constructing a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear.
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Chronic myelogenous leukemia (CML) is caused by the reciprocal chromosomal translocation t(9:22)(q34;q11). This translocation yields BCR-ABL fusion gene on derivative chromosome 22 called as
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TLDR
It is demonstrated that depletion of endogenous MAPK15 expression inhibited B CR-ABL1-dependent cell proliferation, in vitro, and tumor formation, in vivo, therefore providing a novel “druggable” link between BCR-ABl1 and human CML.
Bcr-Abl and Signal Transduction
TLDR
The BCR-ABL oncogene is generated by the Philadelphia (Ph) chromosome translocation, fusing the BCR to the ABL gene, which has constitutive and deregulated tyrosine kinase activity that is critical for transformation of hematopoietic cells.
MUC 1 Oncoprotein Regulates Bcr-Abl Stability and Pathogenesis in Chronic Myelogenous Leukemia Cells
Chronic myelogenous leukemia (CML) results from expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1 heterodimeric protein is aberrantly overexpressed in diverse human
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