A Novel FRET-Based Biosensor for the Measurement of BCR-ABL Activity and Its Response to Drugs in Living Cells
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概要
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Purpose: To develop a novel diagnostic method for the assessment of drug efficacy in CML patients individually, we generated a biosensor that enables the evaluation of BCR-ABL kinase activity in living cells using the principle of fluorescence resonance energy transfer (FRET). Experimental Design: To develop FRET-based biosensors, we utilized CrkL, the most characteristic substrate of BCR-ABL, and designed a protein in which CrkL is sandwiched between Venus, a variant of YFP, and ECFP, so that CrkL intra-molecular binding of the SH2 domain to phosphorylated tyrosine (Y207) increases FRET efficiency. After evaluation of the properties of this biosensor by comparison to established methods including western blotting and flow cytometry, BCR-ABL activity and its response to drugs were examined in CML patient cells. Results: After optimization, we obtained a biosensor that possesses higher sensitivity than that of established techniques with respect to measuring BCR-ABL activity and its suppression by imatinib. Thanks to its high sensitivity, this biosensor accurately gauges BCR-ABL activity in relatively small cell numbers and can also detect less than 1% minor drug-resistant populations within heterogeneous ones. We also noticed that this method enabled us to predict future onset of drug resistance as well as to monitor the disease status during imatinib therapy, using patient cells. Conclusion: In consideration of its quick and practical nature, this method is potentially a promising tool for the prediction of both current and future therapeutic responses in individual CML patients, which will be surely beneficial for both patients and clinicians.
- 2010-08-01
著者
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Takeuchi Jin
Department Of Hematology And Rheumatology Nihon University School Of Medicine
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Kondo Takeshi
Stem Cell Transplantation Center Hokkaido University Hospital
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Asaka Masahiro
Third Department Of Internal Medicine Hokkaido University Graduate School Of Medicine
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Kawamura Takahito
Department Of Medicine Ii Hokkaido University Graduate School Of Medicine
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Maruta Ichiroh
Department Of Hematology And Oncology Hokkaido University Graduate School Of Medicine
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Imamura Masahiro
Department Of Internal Medicine Saiseikai-hita Hospital
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Kondo Takeshi
北海道大学 医学研究科消化器内科学
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Miura Takuya
Department Of Internal Medicine Hakodate Municipal Hospital
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Iwahashi Masahiro
Department Of Internal Medicine Saiseikai-hita Hospital
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Asaka Masahiro
Hokkaido Univ. School Of Medicine Sapporo Jpn
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Kondo Takeshi
Department Of Medicine Ii Hokkaido University Graduate School Of Medicine
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Imamura M
Department Of Internal Medicine Saiseikai-hita Hospital
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Kondo Takeshi
Department Of Gastroenterology And Hematology Hokkaido University Graduate School Of Medicine
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Tanaka Junji
Japan Society For Hematopoietic Cell Transplantation Adult Data Management Committee
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Asaka M
Department Of Gastroenterology Hokkaido University Graduate School Of Medicine
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Kondo Takeshi
Department Of Pathology Laboratory Of Cancer Research Hokkaido University Graduate School Of Medicine
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Tanaka Shinya
Department Of Pathology Laboratory Of Cancer Research Hokkaido University Graduate School Of Medicine
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