Abstract
In targeted therapy using tyrosine kinase inhibitors (TKIs), measurement of TK activities could be beneficial for diagnosis, identification of potential responders, and monitoring treatment efficacy. Here we evaluated the utility of measuring circulating TK (cTK) activity directly from plasma in leukemia patients positive for the BCR-ABL1. Plasma cTK activity was measured from 46 patients with newly diagnosed chronic myelogenous leukemia (CML), 24 with multidrug-resistant CML, 24 with BCR-ABL1-positive acute lymphocytic leukemia (ALL), and 38 healthy donors. Circulating TK activity was significantly higher in CML (median 801.93 U/mL, range 18.10-3932.30 U/mL) and BCR-ABL1-positive ALL patients (median 659.55 U/mL, range 0-1626.90 U/mL) than in healthy donors (median 82.85 U/mL, range 0.63-852.80 U/mL) (P < 0.001). Plasma cTK activity was closely correlated with cellular BCR-ABL1 kinase activation as indicated by phosphorylation of the downstream signaling proteins CRKL (P < 0.001) and STAT-5 (P= 0.003). However, cTK activity was not associated with BCR-ABL1 transcript level and was independent of BCR-ABL1 mutation type. Ex vivo inhibition of imatinib and dasatinib on plasma cTK activity was severely diminished in patients harboring T315I mutation. Ex vivo testing measuring the effect of TKIs on plasma cTK activity thus hold promise as drug sensitivity tests for predicting and monitoring response to specific TKIs.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Benzamides
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Biomarkers, Tumor / blood*
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Dasatinib
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Dose-Response Relationship, Drug
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Enzyme Assays
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Flow Cytometry
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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Gene Expression Regulation, Leukemic
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Humans
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Imatinib Mesylate
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Jurkat Cells
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Mutation
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Nuclear Proteins / metabolism
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Phosphorylation / drug effects
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Piperazines / therapeutic use
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / blood*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / blood*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-abl / blood
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism
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Pyrimidines / therapeutic use
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STAT5 Transcription Factor / metabolism
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Thiazoles / therapeutic use
Substances
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Adaptor Proteins, Signal Transducing
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Benzamides
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Biomarkers, Tumor
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CRKL protein
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Nuclear Proteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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STAT5 Transcription Factor
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Thiazoles
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Imatinib Mesylate
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins c-abl
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Dasatinib